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MicroRNA as a Therapeutic Target in Cardiac Remodeling.

1. Introduction

Myocardial remodeling is one of the major alterations of architecture of the heart that causes the hemodynamic imbalance under pathological stimuli and biomechanical stresses of external stimuli. Myocardial remodeling is a detrimental cardiac problem due to the reason that it is associated with nearly all kinds of heart diseases. The myocardial remodeling process includes physiological changes in structure, dimensions, mass, shape, and functions of the heart as well as cardiac cells. The major contributors in the pathological of myocardial remodeling are cardiac hypertrophy, cardiomyocytes injury, cardiac fibrosis, angiogenesis, and inflammatory response. It is well known that a significant loss of cardiomyocytes due to various insults and slower rate of cardiomyocyte regeneration is the initiative event for the myocardial remodeling in human as well as in animal models [1]. The cardiac inflammation following the myocardial infarction and ischemia reperfusion injury is the primary driving force of delayed cardiac regeneration and pathological cardiac remodeling. The production of extracellular matrix components (ECM) is essential to provide mechanical support to the regenerating heart after cardiac injury. However, the dynamic change in ECM production forces the heart tissue to maladaptive repair, prolonged inflammatory response, and loss of cardiomyocytes, which ultimately leads to cardiac remodeling. The relationship between the risk factors for cardiovascular diseases and myocardial remodeling is shown in Figure 1.

miRNAs are transcripts of noncoding region of the gene. The miRNA era began in 1993 when Lee et al. found the first microRNA in nematode. This field of research has made a tremendous progress in recent years and now it is realized that miRNAs have unavoidable role in both physiological as well as pathological processes [2]. The precursor molecules of miRNAs are called primary miRNAs (pre-miRNAs), which are derived as long fragments in the nucleus by RNA polymerase II. The pre-miRNAs are translocated to the cytoplasm and subsequently processed by different molecular machineries including RNase III-type endonuclease and Dicer, to form a mature double-stranded miRNAs. In maturation process, the pre-miRNAs lose their terminal base pairs and their hairpin structure in order to generate a mature miRNA. The single-stranded form is a fully active mature miRNA, which binds with RNA-induced silencing complexes (RISCs) and specifically binding with its target genes. These binding silences target gene activity at posttranscriptional level [3,4].

Many experimental and clinical studies reveal that the expression of miR is highly altered in various cardiovascular problems and their alterations are linked with modulation of activity and expression of key components of cardiomyocyte growth, survival, and death. Thus, miRNAs are considered as a central part of the development of various cardiac disorders, which subsequently leads to cardiac remodeling and progression to heart failure. In this review, we discuss the impact of alterations of miR expression on the process of pathological cardiac remodeling. For the clear illustration, we divide the adverse cardiac remodeling into the following components: cardiac hypertrophy, cardiac fibrosis, myocardial cell injury, and angiogenesis, which are closely related to the progression of cardiac remodeling and heart failure.

2. miRNA and Cardiac Hypertrophy

Cardiac hypertrophy is one of the major responses to various physiological and pathological stress stimuli in the heart. The major feature of hypertrophic response is an increase in the thickness of the ventricular wall, cardiac dilatation, and heart failure. As the maladaptive hypertrophic response consequently leads to various cardiac problems, many scientific works endeavor to figure out the underlying molecular mechanism of pathological hypertrophy. However, the molecular mechanisms associated with cardiac hypertrophy remain largely unknown [5, 6]. miRNAs play an important role in regulating the cardiac hypertrophic processes. They either negatively or positively modulate hypertrophic signaling and thus indirectly influence the hypertrophy associated cardiac remodeling.

MiR-1 is one of the key regulators of pathological cardiac hypertrophy by targeting multiple signaling molecules in human as well as in experimental animal models. MiR-1 protects heart structure and functions against cardiac hypertrophic responses by directly targeting and inhibiting translation of many signaling molecules including eukaryotic initiation factor 4E (Eif4e), Mef2a, Gata4, and histone deacetylase 6 (HDAC6) [7-9]. MiR-1 also attenuates calcium signaling dependent cardiac hypertrophic response by negatively regulating calmodulin (CAM), one of the key components of calcium signaling, which contributes to the progression of pathological hypotrophy in the heart [7]. The increased circulatory level of heart specific fat binding protein 2 (FABP3) is an indicator of heart enlargement and hypertrophy in patients and miR-1 can directly target FABP3 in cardiomyocytes. A study found that there is an inverse correlation between the expression of miR-1 in myocardial tissue and FABP3 level in circulation [10]. Another research group found that miR-1 inhibits fibulin-2 (Fbln2) expression and thereby it abolishes activation of TGF[beta] signaling and extracellular matrix remodeling in hypertrophic heart [11,12]. MiR-133 is one of the abundantly expressed antihypertrophic miR in both animal and human myocardial tissues. MiR133 blocks hyperthyroidism induced cardiac hypertrophy by suppressing the expression of type 1 angiotensin II receptor (AT1R) [13]. Care et al. (2007) observed that miR-133a attenuates cardiac remodeling by regulating Akt and its downstream signaling molecules such as Cdc42, Rho-A, and Nelf-A/WHSC2 [14]. MiR-10a [15] and miR-497 [16] exert their antihypertrophic effect by blocking translation of Tbx2 and Sirt4, respectively. MiR-223 directly targets cardiac troponin I-interacting kinase (TNNI3K) and inhibits troponin I (cTnI) phosphorylation in cardiomyocytes, which promotes contractility and accumulation of intracellular [Ca.sup.2+] [17]. MiR-455 is an important miR in the developing heart that targets calreticulin to prevent pressure overload induced hypertrophy [18]. MiR-378 suppresses the expression and activities of many growth promoting receptors and signaling pathways, including insulin-like growth factor receptor 1 (IGFR1), growth factor receptor bound protein 2 (Grb2), kinase suppressor of Ras 1 (Ksr1), Ras activity, PI3K-Akt pathway, Mapk1-MAPK signaling, and Raf1-MEK1-ERK1/2 pathway [19, 20] This inhibition is associated with reduction of hypertrophic response in cardiac tissue. MiR-145 showed its negative effect in isoproterenol-induced cellular hypertrophy via regulation of the expression of GATA binding protein 6 (GATA6) [21, 22]. MiR-155 alleviates cardiac hypertrophy and improves heart function by repressing the expression of angiotensin II receptor type 1 (AGTR1) and suppression of its downstream calcium signaling pathways [23]. MiR-212/132 family [24] and miR-23a [25] target Foxo3 transcription factor to mitigate the hypertrophic signal in cardiomyocytes. MiR-29a-3p inhibits ET-1-induced hypertrophic response in cardiomyocytes by directly targeting 3' UTR of NFATc4 [26].

In opposite, many miRNAs play prohypertrophic role in the heart. For instance, miR-208a is a well expressed miR in the heart and it is highly associated with development of cardiac hypertrophy and fibrosis. Hyperthyroidism induces cardiac hypertrophy by promoting the expression of angiotensin type 1 receptor (AT1R). The stimulation of a-MHC mediated expression of miR-208a promotes the expression of AT1R in hyperthyroid condition [27]. Another study found that miR208 regulates the translation of thyroid hormone receptor associated protein 1 (THRAP1) and leads to hyperthyroidism under stress condition. This event consequently enhances [beta]-MHC expression and further aggravates cardiac hypertrophy [28]. MiR-124 effectively represses AngII-induced neonatal cardiomyocytes hypertrophy by blocking the expression of calreticulin (CRT) and glucose-regulated protein (Grp78), an endoplasmic reticulum (ER) stress marker [29]. Several miRNAs reduce the expression of antihypertrophic factors and indirectly contribute to elevation of pathological hypertrophy. MiR-297 negatively regulates the expression of Sigma-1 receptor (Sig-1R) and activates ER stress signaling [30], while miR-17-3p targets metallopeptidase inhibitor 3 (TIMP3), a negative regulator of PTEN-Akt pathway, and resulting in cardiomyocyte hypertrophy [31]. MiR-21 targets suppressors of hypertrophic response by inhibiting translation of SH3 domain-containing protein 2 (SORBS2), PDZ, and LIM domain 5 (PDLIM5) [32]. MiR-155 acts as a prohypertrophic factor by abolishing the expression of Mef2A and Jarid2 in cardiomyocytes and inhibition of miR-155 improves the cardiac function from hypertrophy induced progressive heart failure [33]. MiR-22 acts as a prohypertrophic factor by targeting PTEN, Sirtuin 1 (Sirt1), and histone deacetylase 4 (Hdac4), which are negative regulators of hypertrophic signaling [25, 34, 35]. Interestingly, miR-23a has mutual regulatory role with lysophosphatidic acid (LPA) receptor. LPA can upregulate miR-23a expression by activation of LPA3 dependent PI3K/Akt pathway [36].

In experimental cardiac hypertrophy, MiR-195 downregulates the translation of HMGA1 by targeting its 3' UTR and this inhibition promotes hypertrophic response [37, 38]. Atrogin 1 and muscle RING finger protein 1 (Murf1) are antihypertrophic factors and their expression is downregulated by miR-19a/b family. miR-19b mediates hypertrophic process by activating the PI3K and calcineurin/nuclear factor of activated T cells (NFAT) signaling, which are prohypertrophic pathway that changes phonotype of cardiomyocytes. Interestingly, miR-19b also has the capability to promote cell survival by attenuating the upregulation of NFAT target gene encoding [alpha]-crystallin-B and repression of the proapoptotic gene Bim (Bcl-2-interacting mediator of cell death) caused by endoplasmic reticulum (ER) stress [39]. A study in experimental model of hypertrophy found that miR-27b blocks the expression of peroxisome proliferator-activated receptor [gamma] (PPAR-[gamma]), which can relieve cardiac hypertrophy mediated cardiac dysfunction and heart failure. In pressure overload model of hypertrophy, it was confirmed that antagonists of miR-27b can restore the expression of PPAR-[gamma] and alleviate heart dysfunction in those animals. Surprisingly, transforming growth factor [beta]1 (TGF[beta]1), a hypertrophy stimulant, can regulate the expression of miR-27b. [40]. Sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) is a key calcium transporter responsible for the [Ca.sup.2+] reuptake, which is suppressed by miR-328 during hypertrophic response in cardiomyocytes as well as in hearts of mouse. This leads to upregulation of the calcineurin/NFAT signaling and cardiac dysfunction [41]. Several experimental studies also found that the suppression of expression of hypertrophy associated miRNAs using antagonists (antagomir) attenuates pathological remodeling in the heart. miR-185 favours hypertrophic response by upregulating multiple genes in calcium signaling pathways, including [Ca.sup.2+]/CaM dependent protein kinase IId (Camk2d), sodium/calcium exchanger 1 (Ncx1), nuclear factor of activated T cells, and cytoplasmic calcineurin dependent 3 (Nfatc3) and downregulation of miR-185 can alleviate hypertrophy induced pathological changes in the heart [42]. Similarly, antagonist of miR-101 attenuates experimental cardiac hypertrophy by target the expression of ras-related protein-1A (Rab1A) [43]. The antimir of miR-208a attenuates cardiac remodeling by upregulation of expression Myh7 in pressure overload induced heart failure in rats [44]. Together, these studies reveal that the balance in the expression of certain miRNAs is essential to control the hypertrophic response in cardiomyocytes and preservation of cardiac structure and function. The known microRNAs (miRNAs) in cardiac hypertrophic and their target genes are summarized in Figure 2 and Table 1.

3. miRNA and Fibrosis

Cardiac fibroblast is the most abundant cell type in the heart that comprises about two-thirds of the total number of cardiac cell types. The transient activation and proliferation of cardiac fibroblasts after cardiac injury are vital to maintain cardiac integrity and function. However, the persistence of fibroblast activation process accumulates myofibroblast phenotype in the cardiac tissue and that causes adverse myocardial remodeling and cardiac dysfunction. The relentless availability of growth factors, abundant expression of growth factor receptors, and accumulation of cytoplasmic matrix proteins play a fundamental role in the activation of cardiac fibroblast and fibrotic processes [45, 46]. The other factors such as reactive oxygen species (ROS), inflammatory cytokines and chemokines, and mast cell-derived proteases also play crucial role in the development of myocardial fibrosis (Figure 2). Many miRNAs have influence on fibrogenesis either positively or negatively by modulating the expression/activities of fibrotic signaling molecules in the cardiac tissue.

Transforming growth factor [beta] (TGF[beta]) is a multifunctional cytokine that plays a central role in the development and progression of fibrosis in many tissues including heart. The activation TGF[beta] dependent signaling pathway and relentless expression of TGF[beta] signaling components play crucial role in the expression of extracellular matrix components (ECM) and aggravation of fibrotic response, which consequently leads to ventricular remodeling in the heart. Several miRNAs exert their antifibrotic activity by directly antagonizing the expression and/or activity of TGF[beta] signaling components in cardiac myofibroblasts. MiR-101 blocks excessive production of matrix proteins and proliferation of activated fibroblasts by suppressing expression of TGF[beta]RI and c-Fos. In experimental model, overexpression of miR-101 alleviates deterioration of cardiac performance caused by fibrotic process [47, 48]. MiR-122 can control the expression of TGF-[beta]1, but its expression is downregulated in patients and leads to severe myocardial fibrosis [49]. MiR24 inhibits TGF[beta]-smad2/3 signaling mediated differentiation and migration of cardiac fibroblasts by inhibiting furin, a regulatory protein involved in latent TGF[beta] activation process. A synthetic precursor of miR-24 can improve heart function [50]. Similarly, MiR-98 and miR-19a-3p/19b-3p inhibit fibrogenesis by blocking the expression of TGF[beta]RI and TGF[beta]RII, respectively. These receptors are integral part of ECM production, cardiac fibrosis, and ventricular thickening [51, 52]. The miR-15 family is one of the most important miRNAs involved in the regulation of fibrosis. It encodes six miRNAs (miR-15a, miR-15b, miR-16, miR-195, miR-497, and miR-322). The expression of multiple miR-15 family members targets TGF-[beta]R1, p38, SMAD3, sMaD7, and endoglin to inhibits the TGF-[beta]-pathway. However, the family of miR-15 has negative effect on cardiomyocyte proliferation [53, 54]. Likewise, miR-378 attenuates TGF/Smad/Ras signaling by suppressing the expression of several profibrotic transcription factors such as AP1 transcription factors, cFos, and c-Jun in cardiac fibroblasts. However, this miRNA expression is downregulated in cardiac tissue during fibrotic process by an unknown mechanism [55]. Several miRNAs play profibrotic role by upregulating the expression of TGF[beta] signaling molecules. miR-21 is highly expressed by cardiac fibroblasts in postmyocardial injury condition and its expression accelerates fibrotic process by blocking the expression of TGF[beta]RIII, which is a negative regulator of TGF[beta]1-Smad3 signaling [56]. miR-21 also favours fibrogenic process by inhibiting the expression of sprouty homolog 1 (Spry1), a molecule required for controlling fibroblast growth factor secretion and inhibition of ERK-MAP kinase activity. miR155 increases TGF[beta]1-Smad2 signaling pathway by elevating the level of Smad 2 and resulting in cardiac fibrosis [57]. TGF[beta]1 induces expression of miR-22, which increases the level of Smad4, which is an essential component of Smad complex (Smad2/3/4) that facilitates the translocation to nucleus and induction of downstream genes [58].

Connective tissue growth factor (CTGF) is a key molecule involved in the development and progression of fibrosis by promoting the synthesis of ECM proteins including collagen. miR-133 and miR-30 downregulate CTGF expression and attenuate cardiac fibrosis [59]. miR-26a also attenuates fibrotic process by directly targeting translation of CTGF genes and expression of collagen type I. Interestingly, NF-kB and miR-26a reciprocally regulate each other in the fibrotic heart. The increased expression of NF-kB diminishes levels of miR-26a, while overexpression of miR-26a diminishes NF-kB activation [60]. A recent study found that miR29 acts as an antifibrotic factor by accelerating the expression of multiple extracellular matrix genes including elastin [61], fibrillin 1 (Fbn1), collagen type I, [alpha] 1 and 2 (Col1[alpha]1, Col1[alpha]2), collagen type III, [alpha]1 (Col3[alpha]1), and fibronectin (FBN) [62,63]. Another research group also confirmed the antifibrotic effects of miR29b in angiotensin II induced cardiac fibrosis model [64]. MiR-146a targets VEGF expression and suppresses VEGF dependent proliferation and expansion myofibroblasts [65]. The other miRNAs such as miR-142-3p and miR-433 target high mobility group box 1 (HMGB1), AZIN1, and JNK1, respectively, to ameliorate cardiac fibrosis [66, 67].

Several miRNAs positively modulate myocardial fibrosis by directly upregulating the expression of profibrotic genes or indirectly through suppressing the expression of antifibrotic signaling molecules, which inhibit fibrotic process by either negatively regulating profibrotic factors activity or expression. miR-208 is a cardiac-specific miR whose upregulation is closely related to the development of cardiac fibrosis. MiR-208 induces myocardial fibrosis by upregulating the expression of endoglin, a coreceptor of TGF and [beta]-myosin heavy chain ([beta]-MHC) [68, 69]. A molecular study found that miR-208 specifically contributes to stress dependent expression of [beta]-MHC and cardiac fibrosis. This is partly due to suppression of thyroid hormone receptor associated protein 1 (THRAP1), a coregulator of thyroid receptor, which can positively modulate [alpha]-MHC gene expression and suppression of [beta]-MHC in cardiac tissue [28]. Interestingly, miR-22 acts as a downstream of TGF[beta]1 signaling. TGF[beta]1 induces expression of miR-22, which increases the level of Smad4, an essential component of Smad complex (Smad2/3/4) that facilitates the translocation to nucleus and induction of downstream genes [58]. miR-499 plays a crucial role in the development of myocardial hypertrophy and fibrosis by targeting many intracellular signaling molecules and transcription factors including Akt, MAPKs, Egr1, Egr2, and Fos or promoting Myh7 and Acta1 expressions [68]. miR-125b acts as a profibrotic molecule by targeting apelin, which is one of the key suppressors of cardiovascular remodeling that inhibits TGF[beta] mediated collagen production and Ang II induced plasminogen activator inhibitor type I (PAI-1) [70, 71]. Collectively, these studies reveal that miRNAs play unavoidable role in both controlling and activating fibrogenic processes and cardiac remodeling. The balancing of antifibrotic miRNAs and profibrotic miRNAs is crucial to determine the fibroblast activation, acceleration of fibrotic signaling, accumulation of ECM components, and fibrotic processes. The known miRNAs in cardiac fibrosis and their target genes are summarized in Figure 3 and Table 2.

4. miRNA and Cardiomyocytes Injury

The loss of cardiomyocytes due to injury and their low regenerative capability in the adult heart is the early event responsible for the ventricular dysfunction, fibrosis, and progressive heart failure. Many studies found that chronic cardiac remodeling is highly associated with increasing cardiomyocyte cell death. The damage and/or loss of cardiomyocytes occur in various cardiovascular problems including myocardial infarction, ischemia/reperfusion injury, cardiomyopathy, and cardiac toxicity. However, the mode of cell death mainly depends on the type of insult to the heart. In the last few years, numerous miRNAs have been identified as regulators of cardiomyocytes injury due to their role in apoptosis, autophagy, and inflammatory response. In this part, we summarize the influence of miRNAs on different mode of cell death in cardiomyocytes.

4.1. miRNA and Apoptosis. Apoptosis is the major form of cardiomyocyte death in the failing heart. In cardiomyocytes, apoptosis can be activated by both intrinsic pathway (mediated by mitochondria) and extrinsic pathway (mediated by plasma membrane death receptors). However, these two pathways converge into mitochondria to induce the release of mitochondrial apoptogenic molecules and activation of caspase cascades. The activation of apoptosis is a complex event, which is tuned by highly regulated interaction of proapoptotic molecules. Many cell signaling pathways including the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, p53 pathway, activators of transcription (STAT) pathway, mitogen-activated protein kinase (MAPK) pathway, and stress-activated protein kinase (SAPK) signaling pathway contribute to the activation and regulation of the apoptotic pathway. miRNAs control apoptosis either directly inhibiting expression and translation of proapoptotic molecules or indirectly through regulating the machineries of apoptotic signaling pathways.

Several miRNAs serve as protective factor of cardiomyocyte survival by suppressing/inhibiting the expression of proapoptotic molecules. miR-145 acts on mitochondrial apoptotic pathway by blocking the expression of Bnip3, a mitochondrial apoptosis initiation factor Bnip3. By inhibiting Bnip3 mediated signaling, miR-145 attenuates oxidative stress induced cardiomyocyte cell death caused by [H.sub.2][O.sub.2] or ischemia reperfusion [72]. Interestingly, miR-494 plays vital role in protection against I/R injury induced cell death by activating Akt-mitochondrial signaling pathway and antiapoptotic proteins (FGFR2 and LIF) through inhibition of expression of proapoptotic proteins (PTEN, ROCK1, and CaMKII[delta]) [73]. miR-499 also inhibits mitochondrial pathway of cell death by abolishing calcineurin-mediated dephosphorylation of dynamin-related protein-1 (Drp1) and reducing mitochondrial fission [74]. Another research group found that miR-30 is required to prevent abnormal mitochondrial fission associated cell death. However, the downregulation of miR-30 under oxidative stress positively modulates the expression of p53 and Drp1, which consequently leads to cell death [75]. Surprisingly, miR-30 family can target multiple genes of [beta]1 and [beta]2 adrenergic receptors and G protein [alpha] i subunit (Gi[alpha]2) to regulate [beta]-adrenergic signaling pathway [76]. The mitochondrial morphology associated cell death is regulated by miR-181c, which is inversely correlated with the levels of caspases, Bcl-2, and cytochrome C [77]. In diabetic cardiomyopathy, miR-675 can prevent cardiac apoptosis by suppressing the expression of mitochondrial voltage dependent anion channel 1 (VDAC1), which plays crucial role in activation and release of proapoptotic molecules [78].

Under reticulum stress-associated apoptotic process, the upregulation of miR-185 protects cardiac cells from death by targeting [Na.sup.+]/[H.sup.+] exchanger-1 (Nhe1) [79]. The upregulation of miR-378 enhances cell survival by inhibiting caspase-3 expression in cardiomyocytes during ischemia reperfusion injury [80]. MiR-210 also promotes cardiac cell survival by blocking expression of the negative regulators of VEGF signaling (Efna3 and Ptp1b) and apoptosis inducing factor-mitochondrion associated 3 (AIFM3) [81, 82]. Similarly, miR-21 [83] and miR-328 [84] directly target programmed cell death 4 (PDCD4) gene and Atp2a2, respectively. Bim is a Bcl2 family protein, which positively regulates apoptosis by activating caspase cascade of death. Bim expression is inhibited by miR24 [85] and upregulation of miR-24 decreases apoptosis and necrosis in ischemic myocytes by inhibiting BCL2L11 gene [86]. Interestingly, miR-214 prevents [Ca.sup.2+] overload induced cell death by attenuating several [Ca.sup.2+] signaling molecules including NCX1, CaMKII[delta], CypD, and Bim [87]. In sepsis induced cardiac dysfunction, miR-124 can block cardiomyocyte apoptosis by downregulating the expression of syntaxin-2. However, its expression is suppressed by bacterial LPS under experimental condition [88].

The reduction of blood flow to myocardial tissue produces hypoxia, which imposes oxygen tension and cardiomyocyte cell death. Several miRNAs target hypoxia inducible genes to attenuate or aggravate the oxygen tension induced cardiomyocyte death. miR-199a acts as a master regulator of hypoxia by inhibiting hypoxia inducible factor-1[alpha] (Hif-1[alpha]) expression and reducing oxygen tension. MiR-199a indirectly abolishes increased level of Hif-1[alpha] by blocking the expression of Sirt1, which is required downregulation of prolyl hydroxylase 2, a molecule involved in stabilization of Hif-1[alpha] [89]. miR-363 controls hypoxia inducible cardiac apoptosis via regulation of Notch1 expression and its downstream signaling [90]. Similarly, the hypoxia induced early expression of miR-146b is cardiomyocyte protective by increasing the expression of NF-kB and STaT3, which play cell survival role [91]. MiR-214 protects cardiomyocyte cell survival and tissue damage caused by hypoxia and I/R injury by suppressing PTEN expression activating PI3K-Akt mediated survival signaling [92]. In contrast, the hypoxia inducible expression of miR-200c, miR-92a, and miR-27a promotes cardiomyocyte cell death by targeting GATA-4, Smad 7, and interleukin 10 (IL-10) pathway, respectively [93-95]. GATA4 is a transcription factor required for the cardiomyocyte growth and survival and downregulation of miR-200c promotes GATA-4 dependent expression of antiapoptotic genes such as Bcl2 [93], while inhibition of hypoxia induced increase of miR-92a promotes translation of SMAD7 and blocking NF-kB p65 signaling [94]. miR-138 inhibits expression of Lcn2, a proapoptotic gene by abrogating MLK3/JNK/c-jun signaling pathway [96, 97].

Many miRNAs are upregulated under various pathological conditions in cardiac tissue including myocardial infarction and ischemia/reperfusion injury. They trigger the expression/activity of proapoptotic molecules and cause cardiomyocyte apoptosis. In animal model of ischemia/reperfusion injury, the upregulation of miR-29 inhibits Mcl-2 and enhances Caspase 3 and Bax activity. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR)-[gamma] with pioglitazone abrogates proapoptotic effects of miR-29 and protects cardiac cells from death [98]. miR-122 promotes cardiac apoptosis by inhibiting blockers of caspase-8 and enhancing its expression [99]. Apart from this, miR-378 promotes cardiomyocyte apoptosis by blocking a survival signaling cascade activated by Akt pathway through inhibition of expression of insulin-like growth factor 1 receptor (IGF1R) [100]. Similarly, miR-28 negatively regulates phosphoinositide-dependent kinase-1 (PDK1) and thereby blocks PDK1/Akt/mTOR-dependent signaling of cell survival under oxidative stress condition [101], whereas miR-1 and miR-181c target Bcl-2 expression and favour apoptotic signaling in cardiomyocytes [75,77]. In addition, overexpression of miR-1 inhibits the expression of protein kinase C[epsilon] (PKC[epsilon]) and heat shock protein 60 (HSP60) and that leads to increased expression of caspase-3 in cardiomyocytes under I/R injury [102]. MiR-195 also downregulates Bcl-2 and Sirt1, which subsequently leads to overproduction of ROS to induce cell death in cardiomyocytes [103]. MiR-15 family members play important role in both cardiomyocyte cell proliferation as well as survival. The expression of miR-15 family inhibits a number of cell cycle genes including checkpoint kinase 1 (Chek1) [104], which causes cell cycle arrest and subsequently cell death. miR-28 [105] and miR-34a [106] block the expression of mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2), which activates activating AMPK and Akt-mTOR signaling and protecting cardiomyocytes against I/R injury. The inhibition of this pathway aggravates the ischemic injury in myocardial cells [105]. The age related increase of miR-34a aggravates apoptotic cell death in the heart with myocardial injury by suppressing PNUTS and DNA damage responses. This leads to functional decline of the heart [107]. The known miRNAs in cardiac apoptosis and their target genes are summarized in Figure 4 and Table 3.

4.2. miRNA and Autophagy. Autophagy is an evolutionary conserved and highly regulated cellular recycling program that eliminates damaged intracellular organelles as well as injured cells. Emerging studies indicate that many miRNAs affect autophagy by influencing the expression/translation of different machineries involved in the autophagic process (Figure 5). In mammalian system, the autophagy process is initiated by activation of ULKl or ULK2 complexes. The miRNA-17 family members, miRNA-106b and miRNA-20a, block autophagy process by inhibiting the translation of ULKl by targeting the 3'-UTR of ULKl [108]. Experimental studies have shown that miR-25 [109], miR-17-5p [110], miR-4487, and miR-595 [17] can directly target ULK1, while miR-8853p [111] and miR-26b [112] block autophagy initiation by inhibiting ULK2 [111]. Following the initiation, the vesicle nucleation is one the key processes in autophagy, in which phosphatidylinositol 3-kinase (PI3K) dependent activation and formation of complex composed of VPS15, VPS34, VPS30, and ATG6/BECN1 (Beclin 1) proteins play a central role in vesicle formation. Several miRNAs can modulate the expression of components of above complex and regulate the vesicle nucleation process. miR-30a, miR-384-5p, miR-4093p, and miR-216a directly target the expression of Beclin-1 gene to inhibit vesicle formation [113-117].

The process of vesicle elongation is regulated by two ubiquitin-like protein conjugation systems: Atg5-Atg12-Atg16 protein complex conjugation system and LC3 (microtubule-associated protein 1 light chain 3) conjugation system. Several miRNAs regulate autophagic process by modulating the expression of components of these two ubiquitin-like protein system. Jing et al. found that miRNA-30a/c, miR-181a, miR-130a, miR-374a, and miR-630 inhibit the progression of autophagic process by inhibiting expression of Atg5 and Atg12 [191], whereas miR-181a [119], miR-30a [121], and miR-224-3p [120] only interact with Atg5 mRNA resulting in reduction of its translation. In addition, miR-30d directly targets Atg16 to block the formation of Atg5-Atg12-Atg16 protein complex [122]. miR-519A has the capability to suppress expression of both Atg16 and Atg10 [118]. Several research groups found that miR-375, miR-20a, miR-137, miR-96, miR-188-3p, and miR-199a-5p block autophagic process by directly targeting Atg7, an autophagic protein involved in the formation of Atg7-Atg10 complex [32, 123-127]. Atg4 family is involved in the processing of LC3. miR-376 family members such as miR-376a and miR-376b inhibit translation of Atg4C and attenuate autophagic process [128, 129]. MiR-101 suppresses expression of Atg4D abd blocks Lc3 processing [130]. Wang et al. [131] found that silencing of endogenous miR-382 function in renal mesangial cells can induce LC3-related autophagy. Ursolic acid is shown to improve autophagy and increase the expression of LC3-II to attenuate diabetic mesangial cell injury through attenuated miRNA-21/PTEN/Akt/mTOR signal pathway [132].

Apart from them, MiR-130a and miR-143 interfere the formation of Atg9-Atg2-Atg18 complex by targeting Atg2B and inhibiting autophagosome assembly [133,134]. Another research group found that miRNA-34a attenuates autophagic process by downregulating the expression of Atg9 gene [135]. The fusion of autophagosome-lysosome fusion is mediated by key autophagic proteins such as RAB1B, RAB22A, RAB14, RAB27A, LAMP2, and LAMP3. Many research groups found that miR-502 and miR-451 inhibit RAB1B and RAB14, respectively [136,137]. LAMP2 can be suppressed by miR-207 and miR-487-5p, while miR-205 blocks RAB27A and LAMP3 and interfering autophagic vesicle maturation process [138, 140, 192]. The two other miRNAs such as miR-630 and miR-374a can directly target UVRAG and thus affect the maturation of autophagosomes [118]. The known miRNAs in autophagy and their target genes are illustrated in Figure 5 and Table 4.

4.3. miRNA, Inflammatory Response, and Pyroptosis. The activation and accumulation of immune cells such as macrophage are of the earliest responses to cardiac tissue injury that governs the clearance of cell debris, stimulation of compensatory growth and cardiac tissue regeneration. The macrophage polarization and activation are the key process involved in the determination of the inflammatory response, cardiac tissue injury, angiogenesis, scar formation, and cardiac tissue remodeling [139]. In general, the activation of classical M1 macrophage at early phase initiates inflammatory response by increased production of proinflammatory cytokines and chemokines. However, the polarization of macrophages generates alternative M2 macrophage phenotype, which exerts inflammation suppression, apoptotic cell clearance, and tissue repair [139]. miRNAs modulate the activity of macrophages and they can regulate the expression of several proinflammatory cytokines. miR-155 plays multiple roles in the inflammatory process. miR-155 regulates macrophage polarization by controlling SOCS1 and Akt1 axis [141]. In viral myocarditis, the increased expression of miR-155 blocks macrophage polarization and alternatively activated M2 macrophages phenotype transformation. This results in increased pathogen induced inflammation and cardiac injury [142]. miR-155 also promotes macrophage survival by upregulating the SHIP1-Akt signaling cascade [143]. The increased level of macrophage derived miR-155 acts as paracrine regulator of cardiac fibroblast proliferation as well as inflammatory response following the myocardial infarction induced injury [144]. In contrast, another research group found that miR-155 functions as a negative feedback regulator of immune response by reducing the expression of cytokines by cardiac myocytes during viral infection induced myocarditis [145]. Similarly, miR-155 can block the activity of macrophages by directly targeting proinflammatory NF-[kappa]B signaling transcription factor in atherosclerotic plaque [146]. Apart from this, the colony stimulating factor 1 (CSF-1) dependent expression of miR-21 positively regulates macrophage polarization. It promotes amplification of M2 macrophage phenotype and directly targets proinflammatory molecules [149]. PPAR[gamma] promotes alternative activation and polarization of macrophage (M2) by enhancing the expression of miR-22, which targets Rasa1 and Nfat5 [150]. However, miR-27a switches on M1 macrophage polarization by blocking PPAR[gamma] [151]. mir-375 promotes inflammation induced cardiomyocyte cell death by inhibiting PDK1-Akt signaling and increasing proinflammatory cytokines [152].

miR-125 family is considered as a therapeutic target for the prevention of inflammation. miR-125a and miR-125b directly suppress the expression of tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20), which is a negative regulator of NF-KB signaling [147]. Another research group found that TLR2 and TLR4 dependent upregulation of miR125a-5p suppresses classical pathway of macrophage activation and inflammation. However, this miR-125a-5p stimulates alternative pathways of macrophage polarization and activation [148]. Interestingly, miR-125b has been reported to suppress the activity and stability of TNF-[alpha] transcript and thereby it reduces inflammatory responses [123]. Efferocytosis is a process of the clearance of apoptotic cardiomyocyte by macrophages. This process is vital for clear resolution of inflammatory response and tissue repair after cardiac injury. miR-126 promotes the efferocytosis in myocardial tissue. However, the reduction of its expression under diabetic condition impairs the clearance of dead cardiomyocytes, which consequently leads to prolonged inflammation process [153]. Similarly, miR-145-5p can inhibit the CD40 mediated inflammatory response and cardiomyocyte cell death caused by acute hypoxia. But its expression is downregulated under severe hypoxia condition [154]. In sepsis induced cardiac injury and dysfunction, miR-146a can attenuate NF-kB dependent inflammatory signaling by targeting IRAK and TRAF6 in cardiomyocytes and monocytes [155].

Pyroptosis is a proinflammatory form of cell death, which morphologically resembles apoptotic and necrotic mode of cell death. This mode of cell death is triggered by the activation of inflammasome, which leads to the release of inflammatory cytokines. Caspase-1 is the major effector molecule involved in this form of cell death [193]. miR-30d promotes cardiomyocyte pyroptosis under diabetic cardiomyopathy by repressing Foxo3a and its downstream molecule apoptosis repressor with caspase recruitment domain (ARC), which consequently leads to upregulation of the expression of caspase 1 and proinflammatory cytokines (IL-1 and IL-18) in diabetic cardiomyopathy [64]. In opposite to this, miR-9 inhibits inflammatory cytokine secretion and TNF[alpha] induced pyroptosis by inhibiting the expression of ELAVlike protein 1 (ELAVL1) and this inhibition reduces the expression of NLRP3, caspase-1, and IL-1[beta] [194]. Bauernfeind et al. found that miR-223 negatively regulates NLRP3 inflammasome activity and this inhibition could block the initiation of pyroptosis [195]. Currently, very few reports are available to directly link miRNAs and pyroptosis in cardiac tissue. However, their role in the immune cell activation and inflammatory cytokine expression indicates that more miR would be involved in the regulation of pyroptosis process. The known miRNAs in inflammatory response and their target genes are summarized in Table 5.

5. miRNA and Angiogenesis

Neovascularization is the process of new blood vessel formation, which is generated from vascular endothelial cells (EC). This process is essential for the blood supply and nutrients to the recovered part of tissues after various injury [196]. The vascular regeneration is one of the important pathological features of ventricular remodeling. In pressure overload myocardial hypertrophy, the growth rate of vascular tissue is less than the processes of cardiomyocyte hypertrophy. This leads to a significant decrease in the density and causes formation of thin myocardial blood vessels, which relatively reduces blood supply to the heart and eventually affecting heart function. Emerging evidences reveal that miRNAs play fundamental role in maintaining the vascular integrity, endothelial cell proliferation, migration, blood vessel formation and sprouting in the adult heart in response to injury. Under hypoxia and vascular injury condition, the upregulation of miR-126 activates endothelial cells (EC) and endothelial progenitor cells (EPCs) in order to promote vascular healing and vessel formation. The endothelial specific expression of miR-126 promotes the development and maintenance of vessels by enhancing the expression of angiogenic factors such as VEGF and FGF. This is achieved by directly suppressing Spred-1and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-b), which is a intracellular antiangiogenic signaling [156]. MiR-130a contributes to angiogenesis by suppressing antiangiogenic homeobox gene GAX and HOXA5 in endothelial cells. In addition, miR-130a activates PI3K/Akt dependent signaling by inhibiting PTEN expression and that attenuates remodeling after myocardial infarction induced injury [158, 159]. The miR-17-92 cluster is highly expressed in human endothelial cells. This cluster expresses six miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a-1), which are transcriptionally regulated by c-Myc [160]. The miRNAs such as miR-494 and miR-126-5p act as proangiogenic factors by targeting bone morphogenetic protein 4 (BMP4) [197], while miR-18a downregulates CTGF expression in response to Myc activation and promotes angiogenesis [198, 199]. MR-19a primarily targets angiogenesis-inhibitor, thrombospondin-1 (Tsp1) in vascular system. Likewise, the hypoxia induced upregulation of miR-210 promotes endothelial cell migration and capillary like structure formation by targeting Receptor Tyrosine Kinase Ligand Ephrin-A3 and PTP1b [81,161,162]. miR-126 also contributes to vascular angiogenesis through targeting Cysteine-rich 61 (CCN1) in PTEN/Akt pathway [157]. miR-146a promotes angiogenesis by increasing the expression of VEGF and reducing the fibrotic process at injury site [65].

The growth factors upregulate miR-296 and this upregulation favours angiogenesis by reducing levels of hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) through targeting HGS mRNA, which is responsible for degradation of angiogenic receptors such as VEGFR2 and PDGFRb in endothelial cells [163]. Sonic hedgehog (Shh) signaling is involved in the formation of large-diameter vessel by inducing expression of angiogenic cytokines, including VEGF and angiopoietin-1 (Ang-1) and Ang-2 (Ang-2). It is well known that suppressor of fused (SuFu) is a negative regulator Shh signaling. The upregulation of miR-378 promotes cell survival, tumor growth, and angiogenesis by suppressing SuFu and Fus-1 expression [164]. In addition, increased level of miR-378 expression stimulates endothelial cell angiogenic activity [165]. In experimental animal model, the endothelial expression of miR-132 displayed angiogenic potential by suppressing endothelial p120RasGAP expression and promoting Ras activation, which is required for the induction of neovascularization [166]. miR-23 and miR27 promote angiogenesis by inhibiting two antiangiogenic factors such as Sprouty2 and Sema6A proteins [167], while miR-27b expression accelerates angiogenesis by regulating translation of Dll4/Notch axis, PPAR[gamma] and its downstream effectors [168]. Some miRNAs play distinct role in MI heart. For instance, miR-24 has displayed that different activities depend on the cell types in cardiac tissue. In the postinfarct heart, miR-24 enhances survival, proliferation, and angiogenic function of EC by targeting GATA2, p21-activated kinase PAK4, and eNOS. However, it has detrimental role on cardiomyocytes and fibroblasts by inducing cell death [169,170].

Several miRNAs oppose the angiogenic process in endothelial cells. miR-214 prevents cardiac angiogenesis by reducing the expression of X-box binding protein 1 (XBP1); an important transcription factor contributes to endothelial cells proliferation and tube formation [171]. In response to stress, the upregulation of miR-34 family members (miR-34a, miR-34b, and miR-34c) [172], in particular, miR-34a, stimulates endothelial progenitor cell senescence and impedes its angiogenic activity through attenuation of the expression of silent information regulator 1 (SIRT1) [173, 174]. In animal model of MI, silencing of miR-34 family attenuates MI-induced pathological left ventricular remodeling after MI and improves cardiac function by suppressing vascular endothelial growth factors (VEGF), vinculin, protein Ofucosyltransferase 1 (Pofut1), Notch1, and semaphorin 4B (Sema4b) [172]. By targeting the proangiogenesis TGFb-1, miR-29a and miR-101a inhibit TGF[beta] pathway in endothelial cells in MI rats [175]. Overexpression of miR-15b-5p suppresses arteriogenesis and angiogenesis in mice by directly targeting protein kinase B-3 (AKT3) [176]. Some miRNAs play distinct role in MI heart. For instance, miR-24 has displayed that different activities depend on the cell types in cardiac tissue. In the postinfarct heart, miR-24 enhances survival, proliferation, and angiogenic function of EC by targeting GATA2, p21-activated kinase PAK4, and eNOS. However, it has detrimental role in cardiomyocytes and fibroblasts by inducing cell death [169,170].

miR-100 has antiangiogenic function by blocking mTOR signaling in endothelial and vascular smooth muscle cells, and its inhibition promotes the regulation of revascularization [177]. EMT is one of the major mechanisms for the development and progression of fibrosis. It is well known that ZEB1/SIP1 is a suppressor of E-cadherin and upregulation of ZEB1/SIP leads to the loss of epithelial phenotype. Surprisingly, miR-200b and ZEB1/SIP1 have a feedback loop regulation to control epithelial-mesenchymal transition (EMT) and increased expression of miR-200b can suppress ZEB1/SIP1 during EMT [178, 179]. In endothelial cells, miR-200b regulates angiogenic signals by targeting VEGF signaling receptors including VEGFR2, Flt1, KDR, and GATA binding protein 2 (GATA2) [180,181].

Several other miRNAs such as miR-15a, miR-16, and miR-424 target FGF and VEGF signaling components and impose antiangiogenic effects. MiR-15a suppresses FGF2 and VEGF expression, but miR-16 and miR-424 block VEGFR2 and FGFR1 receptor expression in endothelial cells [183, 184]. When the glucose availability is high and growth factor level is low, the endothelial expression of miR-503 is increased, which causes impairment of endothelial function and angiogenesis via directly inhibiting molecules involved in cell proliferation and survival proteins such as cdc25A and CCNE1 [182]. The upregulation of miR-320 expression suppresses insulin-like growth factor-1 (IGF-1) activity in myocardial microvascular endothelial cells and thus impaired angiogenesis in diabetic condition [185]. Astonishingly, the expression of miR-320 by cardiomyocytes controls endothelial function under diabetic condition. In experimental diabetic animals, miR-320 is transferred from cardiomyocytes to endothelial cells by exosomal activity and this transfer regulates endothelial cells migration and tube formation by downregulating IGF-1, Hsp20, and Ets2 [186]. miR-329 abrogates angiogenesis by targeting CD146, an endothelial adhesion molecule required to maintain endothelial cell integrity [187]. In cardiac ischemic condition, miR-92a targets integrin subunits a5 (ITGA5) and causes blockage on angiogenesis, which worsens the ischemic injury [188, 189]. The suppression of miR-92a with antagonist after ischemia reperfusion injury improves the functional recovery of damaged tissue by promoting blood vessel growth [190]. The known miRNAs involved in angiogenesis and their target genes are summarized in Figure 6 and Table 6.

6. Conclusion

Myocardial remodeling due to various insults to the heart is a multifactorial and complex process. To prevent and manage the cardiac dysfunction due to postinjury related cardiac remodeling, it is important to have a clear understanding about the occurrence, development, and progression of cardiac remodeling in the injured heart. Numerous research findings in recent years suggest that miRNAs have unavoidable role in cardiac structure remodeling by differentially regulating thousands of different mRNAs. Many miRNAs have been proposed as prognosis factors and therapeutic tools for myocardial remodeling. Thus, miRNA-based strategies can be a promising approach to target network of myocardium remodeling related genes. In recent years, the pharmacological development of miRNA inhibitors/activators such as miR-mimics, antagomiRs, and decoys to manipulate miRNAs expression level has made a significant progress to utilize them as therapeutic tools for cardiac failure caused by myocardial remodeling. In experimental models mimicking human heart diseases, the exogenous administration of miRNA inhibitors or miRNA mimics can alleviate the remodeling process and improve cardiovascular disease. However, specificity, half-life of these molecules, efficiency, and route of administration are the major challenge to bring them from the workbench to the bedside. By solving these issues by joint efforts of basic researchers and clinical scientist, miRNA could be better and most effective therapeutic regimen to manage cardiovascular problems associated with cardiac remodeling.

Conflicts of Interest

The authors declare no conflicts of interest.


This work was supported by the China Postdoctoral Science Foundation Funded Projects (2016M592133) and (2016M592132); Qingdao Postdoctoral Application Research Funded Project (2016069); the National Science Foundation for Distinguished Young Scholars of China (81600244).


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Chao Chen, Murugavel Ponnusamy, Cuiyun Liu, Jinning Gao, Kun Wang, and Peifeng Li

Center for Developmental Cardiology, Institute for Translational Medicine, Qingdao University, Dengzhou Road 38, Qingdao 266021, China

Correspondence should be addressed to Kun Wang; and Peifeng Li;

Received 3 May 2017; Revised 23 July 2017; Accepted 9 August 2017; Published 28 September 2017

Academic Editor: Kai Chen

Caption: Figure 1: The risk factors for cardiovascular diseases and myocardial remodeling.

Caption: Figure 2: MicroRNAs (miRNAs) in cardiac hypertrophic pathways. Arrows colored in red indicate the functions of depression; arrows colored in green indicate the functions of activation. Abbreviations for mRNAs: AGTR1: angiotensin II receptor type 1; Camk2d: calcium/calmodulin-dependent protein kinase II delta; Cdc42: cell division cycle 42; c-Fos: proto-oncogene protein; CRT: calreticulin; Foxo3: Forkhead box O3; Gata4: GATA binding protein 4; GATA6: GATA binding protein 6; Grb2: growth factor receptor bound protein 2; Hdac4: histone deacetylase 4; HMGA1: high mobility group AT-hook 1; NFAT: nuclear factor of activated T cells; IGF-1: insulin-like growth factor 1; IGF1R: insulin-like growth factor 1 receptor; Jarid2: jumonji and AT-rich interaction domain-containing protein 2; Ksr1: kinase suppressor of ras 1; LPA1: lysophosphatidic acid receptor 1; Mapk1: mitogen-activated protein kinase 1; Murf1: tripartite motif- containing 63; NCX1: sodium/calcium exchanger 1; Nfatc3: nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 3; Ppar[gamma]: peroxisome proliferator-activated receptor [gamma]; PTEN: phosphatase and tensin homolog; p300: E1A binding protein p300; Rab1A: Ras-related protein Rab 1a; Serca2a: Sarco/endoplasmic reticulum [Ca.sup.2+]-ATPase 2a; SIRT1: Sirtuin 1; SMAD4: SMAD family member 4; SORBS2: SH3 domain- containing protein 2; TGF-[beta]R1: transforming growth factor [beta] receptor 1; TNNI3K: troponin I type 3 interacting kinase; cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; PKG: cGMP-dependent protein kinase; CAM: calmodulin; CTnT: cardiac troponin T; NPs: natriuretic peptides.

Caption: Figure 3: MicroRNAs (miRNAs) in cardiac fibrosis pathways. Arrows colored in red indicate the functions of depression; arrows colored in green indicate the functions of activation. Abbreviations for mRNAs: [beta]- MHC: beta myosin heavy chain; COL1: collagen, type 1; Col1[alpha]1: collagen, type 1 [alpha] 1; Col1[alpha]2: collagen, type 1 [alpha] 2; Col3[alpha]1: collagen, type 3 [alpha] 1; CTGF: connective tissue growth factor; IGF-1: insulin-like growth factor 1; IGF-1R: insulin-like growth factor 1 receptor; p38: Tumor protein p38; ROCK1: Rho associated coiled-coil containing protein kinase 1; SMAD3: SMAD family member 3; SMAD2: SMAD family member 2; SMAD7: SMAD family member 7; Spry1: sprouty homolog 1; TGF-[beta]1: transforming growth factor 1; TGF-[beta]R1: transforming growth factor [beta] receptor 1; TGF[beta]RIII: transforming growth factor [beta] receptor III; THRAP1: mediator complex subunit 13; ERK: extracellular regulated protein kinases; MAPK: mitogen-activated protein kinase; AG2R: anterior gradient-2.

Caption: Figure 4: MicroRNAs (miRNAs) in cardiac apoptosis pathways. Arrows colored in red indicate the functions of depression; arrows colored in green indicate the functions of activation. Abbreviations for mRNAs: AIFM3: apoptosis inducing factor; Akt: protein kinase B; ALDH2: aldehyde dehydrogenase 2; Bcl-2: B-cell CLL/lymphoma 2; Bim: Bcl2 like 11; Bnip3: Bcl2/adenovirus E1B19 kDa interacting protein 3; [beta]1AR: adrenoceptor [beta]1; [beta]2AR: adrenoceptor 2; CaMKII[delta]: calcium/calmodulin-dependent protein kinase II, [delta]; Chek1: checkpoint kinase 1; CypD: Cyclophilin+D; FGFR2: fibroblast growth factor receptor 2; Foxo3: Forkhead box O3; Gi[alpha]2: G protein [alpha] i subunit; Hif-1[alpha]: hypoxia inducible factor 1, [alpha] subunit; Hsp60: heat shock protein 60; HSP70: heat shock protein 70; IGF-1R: insulin-like growth factor 1 receptor; IL-10: interleukin 10; mTOR: mechanistic target of rapamycin; NCX1: sodium/calcium exchanger 1; Nhe1: [Na.sup.+]/[H.sup.+] exchanger 1; PDCD4: programmed cell death 4; PDK1: 3-phosphoinositide-dependent protein kinase-1; PKCe: protein kinase c beta1; PTEN: phosphatase and tensin homolog; Ptp1b: Protein Tyrosine Phosphatase-1B; P53: tumor protein p53; p65: tumor protein p65; Rho-A: Ras homolog family member A; ROCK1: Rho associated coiled-coil containing protein kinase 1; SIRT1: Sirtuin 1; TNFR1: tumor necrosis factor receptor superfamily member 1; TNF: tumor necrosis factor; JNK: c-Jun N-terminal kinase; SRF: serum response factor.

Caption: Figure 5: miRNAs in cardiac Autophagy pathways. Abbreviations for mRNAs: AMPK: adenosine 5'-monophosphate- (AMP-) activated protein kinase; ATG: AuTophaGy; UVRAG: UV radiation resistance associated gene; VSP: venom serine protease; LAMP2: lysosomal associated membrane protein 2.

Caption: Figure 6: MicroRNAs (miRNAs) in angiogenesis pathways. Arrows colored in red indicate the functions of depression; arrows colored in green indicate the functions of activation. Abbreviations for Dll4: delta-like protein 4; Efna3: ephrin A3; eNOS: endothelial nitric oxide synthase; FGF2: fibroblast growth factor 2; Foxo1: Forkhead box O1; GATA2: GATA binding protein 2; Gata4: GATA binding protein 4; GAX: gaseous oxygen; HGS: hepatocyte growth factor-regulated tyrosine kinase substrate; Hif-1a: hypoxia inducible factor 1, a subunit; HOXA5: homeobox A5; IGF-1: insulin-like growth factor 1; IGF-1R: insulin-like growth factor 1 receptor; mTOR: mechanistic target of rapamycin; PIK3R2: phosphoinositol-3 kinase regulatory subunit 2; PTEN: phosphatase and tensin homolog; RasGAP: Ras GTPase- activating protein; Sema6A: semaphorin 6A; SIP1: Smad interacting protein 1; SIRT1: Sirtuin 1; Sprouty2: sprouty homolog 2; VEGF: vascular endothelial growth factor; VEGFR2: vascular endothelial growth factor receptor 1; XBP1: X-box binding protein 1; ZEB1: zinc finger E-box- binding homeobox 1; RTK: receptor tyrosine kinase; Casp9, caspase 9; Casp3, caspase 3; ERK: extracellular regulated protein kinases; Spread-1: Sprouty-related, EVH1 domain-containing protein 1; PDGFR[beta]: platelet-derived growth factor receptor [beta].
Table 1: Summary of reported miRNAs and their targets in cardiac

miRNAs          Targets                 Effector cells


miR-1            Eif4e             C57B1/6 mouse and NMCMs
                  Cdk6               NRVCs and ACC mouse
                 HDAC6              NRCMs and Wistar rats
                  CAM                 TG mouse and NRVMs
                 Mef2a                TG mouse and NRVMs
                 Gata4                TG mouse and NRVMs
                 FABP3               NMCMs and TAC mouse
                 Fbln2                      NMCMs

miR-10a           Tbx5               TAC mouse and NRVMs

miR-497          Sirt4               TAC mouse and NRVMs

miR-133           AT1R            Male Wistar rats and NRCMs
                 Cdc42,              NMCMs and TAC mouse
                 Rho-A,              NMCMs and TAC mouse
              Nelf-A/WHSC2           NMCMs and TAC mouse

miR-223          TNNI3K              NRCMs and TAC mouse

miR-455           CRT                     TAC mouse

miR-378          Mapk1               NRCMs and TAC mouse
                 IGF1r               NRCMs and TAC mouse
                  Grb2               NRCMs and TAC mouse
                  Ksr1               NRCMs and TAC mouse

miR-145          GATA6               NRCMs and TAC mouse

miR-29a-3p       NFATc4                   H9c2 cell

miR-21-3p        SORBS2                NRVMs and NRCFs
                  PDZ                  NRVMs and NRCFs
                 PDLIM5                NRVMs and NRCFs

miR-208           AT1R            Male wistar rats and NRCMs
                 THRAP1                    TG mouse
                  Myh7       Adult male Dahl salt-sensitive rats

miR-124          Grp78                      NRCMs

                  CRT                       NRCMs

miR-297          Sig-1R               TAC rat and NRVMs

miR-17-3p        TIMP3              NRVMs and C57BL/6 mice

miR-155          Mef2A               TAC rat and KO mice
                 Jarid2              TAC rat and KO mice
                 AGTR1                  Rat H9C2 cell

miR-212/132      Foxo3             H9c2 cells and TAC mouse

miR-22           Hdac4                  NRVCs, miR-22
                                           KO mouse
                  Pten                      NRVCs
                 Sirt1                  NRVCs, miR-22
                                           KO mouse

miR-23a         Foxo3a,            NMCMs, TAC and TG mouse
                  LPA1                      NMCMs

miR-195          HMGA1                      NRVCs

               atrogin1,             NRVCs and TAC mouse
                 Murf1               NRVCs and TAC mouse

miR-27b       Ppar[gamma]          NRVCs, TAC and TG mouse

miR-328         Serca2a            NRVCs, TAC and TG mouse

miR-185          Camk2d              NRVMs and TAC mouse

                  Ncx1               NRVMs and TAC mouse
miR-101          Nfatc3              NRVMs and TAC mouse
                 Rab1A                     TAC rat

miRNAs          Targets         Signal pathways       References


miR-1            Eif4e            Translation           [7-12]
                  Cdk6          CDKs-Rb pathway
                 HDAC6        Chromatin modifying
                  CAM          Calcium signaling
                 Mef2a         Calcium signaling
                 Gata4         Calcium signaling
                 FABP3               PPAR
                 Fbln2                ECM

miR-10a           Tbx5           transcription           [15]

miR-497          Sirt4               AMPK                [16]

miR-133           AT1R             ERK-MAPK            [13,14]
                 Cdc42,              MAPK
                 Rho-A,            cGMP-PKG
              Nelf-A/WHSC2       Transcription

miR-223          TNNI3K        Calcium signaling         [17]

miR-455           CRT          Calcium signaling         [18]

miR-378          Mapk1               MAPK              [19, 20]
                 IGF1r               MAPK
                  Grb2               MAPK
                  Ksr1               MAPK

miR-145          GATA6             cGMP-PKG            [21, 22]

miR-29a-3p       NFATc4            cGMP-PKG              [26]

miR-21-3p        SORBS2          Transcription           [32]
                  PDZ            Transcription
                 PDLIM5          Transcription

miR-208           AT1R             ERK-MAPK          [27, 28, 44]
                 THRAP1         Thyroid hormone

miR-124          Grp78       Reticulum (ER) stress       [29]
                  CRT          Calcium signaling

miR-297          Sig-1R       ER stress signaling        [30]

miR-17-3p        TIMP3         PTEN-AKT pathway          [31]

miR-155          Mef2A        Calcineurin pathway      [23, 33]
                 Jarid2       Calcineurin pathway
                 AGTR1         Calcium signaling

miR-212/132      Foxo3             PI3K-Akt              [24]

miR-22           Hdac4               AMPK            [25, 34, 35]

                  Pten             PI3K-AKT
                 Sirt1               AMPK

miR-23a         Foxo3a,            PI3K-AKT            [25, 36]
                  LPA1             PI3K-AKT

miR-195          HMGA1                                 [37, 38]

               atrogin1,       calcineurin/NFAT          [39]
                 Murf1                PKC

miR-27b       Ppar[gamma]            PPAR                [40]

miR-328         Serca2a            cGMP-PKG              [41]

miR-185          Camk2d             Calcium              [42]

                  Ncx1             cGMP-PKG              [43]
miR-101          Nfatc3            cGMP-PKG
                 Rab1A               MAPKK

LPA1: lysophosphatidic acid receptor 1; Mapk1: mitogen-activated
protein kinase 1; Murf1: tripartite motif-containing 63; NCX1: sodium-
calcium exchanger 1; Nfatc3: nuclear factor of activated T cells,
cytoplasmic, calcineurin dependent 3; NFATc4: nuclear factor of
activated T cells 4; PDLIM5: PDZ and LIM domain 5; Ppar[gamma]:
peroxisome proliferator-activated receptor [gamma]; p300: E1A binding
protein p300; Rab1A: Ras-related protein Rab 1a; RasGAP: Ras GTPase-
activating protein; Rheb: Ras homolog enriched in brain; Rho-A: Ras
homolog family member A; Serca2a: Sarco-endoplasmic reticulum
[Ca.sup.2+]-ATPase 2a; SORBS2: SH3 domain-containing protein 2; Sox6:
sex-determining region Y box 6; THRAP1: mediator complex subunit 13;
TNNI3K: troponin I type 3 interacting kinase; NRVCs: neonatal rat
ventricular cardiomyocytes; AAC: abdominal aortic constriction; TBX5:
T-box 5; NRCMs: neonatal rat cardiomyocytes; SORBS2: SH3 domain-
containing protein 2; PDLIM5: PDZ and LIM domain 5; NRVMs: neonatal
ratventricular myocytes; NRCFs: neonatal rat cardiac fibroblasts.

Table 2: Summary of reported miRNAs and their targets in cardiac

miRNAs                 Targets              Effector cells


miR-101a            TGF-[beta]R1,          NRCFs and MI rat
                        c-Fos              NRCFs and MI rat

miR-133/30              ctgf            RCMs, RCFs and Ren2 rat

miR-24                  Furin              MCFs and MI mouse

                       Elastin             RCFs and MI mouse
                        Fbn1               RCFs and MI mouse
miR-29              Coll[alpha]l           RCFs and MI mouse
                    Col1[alpha]2           RCFs and MI mouse
                    Col3[alpha]1,          RCFs and MI mouse
                        FBN,               RCFs and MI mouse

miR-146a                VEGF                     hMSCs

miR-98               TGF[beta]R1                 HCFs

miR-433                 AZIN1

miR-142-3p              HMGB1                 M6200 cells

miR-29b              Tgf[beta]1,                 MCFs

miR-19a-3p/19b-3p   TGF[beta] RII                HCFs

miR-22                  Smad4                    MCFs

miR-378              TGF-[beta]1       TAC mouse NMCMs and NRCFs

miR-26a                 COL1,       NRCFs, TAC and miR-26a TG mouse
                        CTGF        NRCFs, TAC and miR-26a TG mouse

                    TGF-[beta]R1          MI mouse and NMCMs
miR-15 family            p38              MI mouse and NMCMs
                        SMAD3             MI mouse and NMCMs
                        SMAD7             MI mouse and NMCMs
                      Endoglin            MI mouse and NMCMs


miR-21                  Spry1        NRCFs, NRCMs, TAC and TG mous
                    TGF[beta]RIII         MI mouse and NRCFs

                      Endoglin            TAC mouse and RCFs
miR-208a                b-MHC             TAC mouse and RCFs
                       THRAP1                  TG mouse

                         Akt                     NRCFs
                        MAPKs                    NRCFs
                        Egr1                     NRCFs
miR-499                 Egr2                     NRCFs
                         Fos                     NRCFs
                        Myh7                     NRCFs
                        Acta1                    NRCFs

miR-122              TGF-[beta]1                 HCFs

miR-125b               Apelin            HCFs, TAC and Ang II
                                             induced mouse

miRNAs                 Targets             Signal pathways


miR-101a            TGF-[beta]R1,        TGF[beta] signaling
                        c-Fos                   MAPK

miR-133/30              ctgf             TGF[beta] signaling

miR-24                  Furin            TGF[beta] signaling

                       Elastin      Protein digestion/absorption
                        Fbn1                     ERK
miR-29              Coll[alpha]l                 ERK
                    Col1[alpha]2                 ERK
                    Col3[alpha]1,                ERK
                        FBN,                     ERK

miR-146a                VEGF                    VEGF

miR-98               TGF[beta]R1              TGF[beta]

miR-433                 AZIN1                 TGF[beta]
                        JNK1                  TGF[beta]

miR-142-3p              HMGB1        TGF-[beta]/Smad3 signaling

miR-29b              Tgf[beta]1,              TGF[beta]

miR-19a-3p/19b-3p   TGF[beta] RII        TGF[beta] signaling

miR-22                  Smad4            TGF-[beta]-pathway

miR-378              TGF-[beta]1         TGF/Smad signaling

miR-26a                 COL1,                 PI3K-AKT
                        CTGF                     ECM

                    TGF-[beta]R1         TGF-[beta]-pathway
miR-15 family            p38             TGF-[beta]-pathway
                        SMAD3            TGF-[beta]-pathway
                        SMAD7            TGF-[beta]-pathway
                      Endoglin           TGF-[beta]-pathway


miR-21                  Spry1                 ERK-MAPK
                    TGF[beta]RIII    TGF[beta]1-Smad3 signaling

                      Endoglin           TGF-[beta]-pathway
miR-208a                b-MHC            TGF-[beta]-pathway
                       THRAP1              Thyroid hormone

                         Akt                     Akt
                        MAPKs                   MAPK
                        Egr1                     ERK
miR-499                 Egr2                     ERK
                         Fos                    MAPK
                        Myh7                     ERK
                        Acta1                   Smads

miR-122              TGF-[beta]1              TGF[beta]

miR-125b               Apelin                 TGF[beta]

miRNAs                 Targets       References


miR-101a            TGF-[beta]R1,     [47, 48]

miR-133/30              ctgf            [59]

miR-24                  Furin           [50]

                       Elastin        [61-63]
miR-29              Coll[alpha]l

miR-146a                VEGF            [65]

miR-98               TGF[beta]R1        [51]

miR-433                 AZIN1           [67]

miR-142-3p              HMGB1           [66]

miR-29b              Tgf[beta]1,        [64]

miR-19a-3p/19b-3p   TGF[beta] RII       [52]

miR-22                  Smad4           [58]

miR-378              TGF-[beta]1        [55]

miR-26a                 COL1,           [60]

                    TGF-[beta]R1      [53, 54]
miR-15 family            p38


miR-21                  Spry1         [56, 57]

                      Endoglin      [28, 68, 69]
miR-208a                b-MHC

                         Akt            [68]
miR-499                 Egr2

miR-122              TGF-[beta]1        [49]

miR-125b               Apelin         [70, 71]

Akt: protein kinase B; [beta]-MHC: beta myosin heavychain; c-Fos:
proto-oncogene protein; COL1: collagen, type 1; Col1[alpha]2:
collagen, type 1 [alpha] 2; Col3[alpha]1: collagen, type 3 [alpha] 1;
CTGF: connective tissue growth factor; Egr1: early growth response
protein 1; Egr2: early growth response protein 2; FBN: fibrillin;
Fbn1: fibrillin 1; MAPKs: mitogen-activated protein kinases; p38:
tumor protein p38; SMAD3: SMAD family member 3; SMAD2: SMAD family
member 2; SMAD7: SMAD family member 7; Spry1: sprouty homolog 1;
TGF[beta]: transforming growth factor [beta]; TGF-[beta]1:
transforming growth factor [beta]1; TGF-[beta]R1: transforming growth
factor [beta] receptor 1; TGF[beta]RIII: transforming growth factor
[beta] receptor III; THRAP1: mediator complex subunit 13; RCFs: rat
cardiac fibroblasts; MCFs: mouse cardiac fibroblasts; HCF: human
cardiac fibroblasts; hMSCs: human mesenchymal stem cells; HBMVECs:
human brain microvascular endothelial cells.

Table 3: Summary of reported miRNAs and their targets in cardiac

miRNAs             Targets                 Effector cells


miR-145             Bnip3                    I/R mouse

miR-199a        Hif-1[alpha],                  NRCMs
                    Sirt1                      NRCMs

miR-21              PDCD4                      NRCMs

miR-328            Atp2a2                    H9C2 cells

miR-214             NCX1             NRCM and miR-214 KO mouse
                    pten                     I/R mouse

miR-24               Bim                       NMCMs

miR-146b           RNase L                   H9c2 cells

miR-378           Caspase-3            H9c2 cells and AMI rat

miR-494             PTEN                  miR-494 TG Mouse
                    ROCK1                 miR-494 TG Mouse
                CaMKII[delta]             miR-494 TG Mouse
                    FGFR2                 miR-494 TG Mouse
                     LIF                  miR-494 TG Mouse

miR-499             Drp1                 Male C57BL/6 mice

miR-185             Nhe1                       NRVMs

miR-30 family    [beta]1AR,     MI rat, DOX-induced HF rat, ARCM and
                 [beta]2AR,                  H9c2 cells
                 Gi[alpha]2,    MI rat, DOX-induced HF rat, ARCM and
                     P53                     H9c2 cells
                    Drp1        MI rat, DOX-induced HF rat, ARCM and
                                             H9c2 cells

miR-210            Efna3,       Mouse HL-1 cardiomyocytes and adult
                                              FVB mice
                    Ptp1b        Mouse HL-1 cardiomyocytes, adult
                                              FVB mice
                    AIFM3             H9c2 cells,neonatal rat
                                       cardiomyocytes (NRCM)

miR-92a           NF-kB p65                rat H9c2 cells

miR-675             VDAC1                       DCM

miR-138             Lcn2                     HL-1 cells

miR-124             STX2                  Male BALB/c rats


miR-1               HSP60           LNA-antimiR-1 treated mouse
                    Bcl-2              H9c2 cells and I/R rat
                PKC[epsilon]        LNA-antimiR-1 treated mouse

miR-200c           GATA-4                      NMCMs

miR-363            Notch1                  Rat H9C2 cell

miR-122           caspase-8                    NMCMs

miR-181c            Bcl-2                      NMCMs

miR-15              Chek1            C57BL/6 mice and TG mouse

miR-34a             pnuts                 NRCMs and MI rat
                    ALDH2                 NRCMs and MI rat

miR-378             IGF1R               NMCMs and H9C2 cells

miR-27a             IL-10        Sprague-Dawley rats and H9c2 cell

miR-29               PIO                     H9c2 cells

miR-28              PDK1                       NMCMs
                    ALDH2                      NMCMs

miR-195             Sirt1             C57BL/6 mouse and NMCMs
                    Bcl-2             C57BL/6 mouse and NMCMs

miRNAs             Targets               Signal pathways


miR-145             Bnip3                     FOXO

miR-199a        Hif-1[alpha],                 mTOR
                    Sirt1                     AT1R

miR-21              PDCD4                     NF-kB

miR-328            Atp2a2

miR-214             NCX1                Calcium signaling
                    pten                    PI3K-AKT

miR-24               Bim             Mitochondrial apoptosis

miR-146b           RNase L                    NF-kB

miR-378           Caspase-3                   MAPK

miR-494             PTEN                    PI3K-AKT
                    ROCK1                   cGMP-PKG
                CaMKII[delta]                 HIF1
                    FGFR2                   PI3K-AKT
                     LIF                       TNF

miR-499             Drp1              Mitochondrial pathway

miR-185             Nhe1                      cAMP

miR-30 family    [beta]1AR,         [beta]-adrenergic pathway
                 Gi[alpha]2,        [beta]-adrenergic pathway
                    Drp1            [beta]-adrenergic pathway

                                      mitochondrial pathway

miR-210            Efna3,                VEGF signaling

                    Ptp1b                VEGF signaling

                    AIFM3            Mitochondrial apoptosis

miR-92a           NF-kB p65                   NF-kB

miR-675             VDAC1            Mitochondrial apoptosis

miR-138             Lcn2             Mitochondrial apoptosis

miR-124             STX2              miR-124a/STX2 pathway


miR-1               HSP60                RNA degradation
                    Bcl-2            Mitochondrial apoptosis
                PKC[epsilon]                cGMP-PKG

miR-200c           GATA-4                   cGMP-PKG

miR-363            Notch1                Notch signaling

miR-122           caspase-8                 ERK-MAPK

miR-181c            Bcl-2            Mitochondrial apoptosis

miR-15              Chek1

miR-34a             pnuts               Oxidative stress
                    ALDH2               Oxidative stress

miR-378             IGF1R                     MAPK

miR-27a             IL-10        Interleukin 10 (IL-10) pathway

miR-29               PIO                      PPAR

miR-28              PDK1        PDK1/Akt/mTOR-dependent signaling
                    ALDH2         AMPK and Akt-mTOR signaling.

miR-195             Sirt1                     AMPK
                    Bcl-2            Mitochondrial apoptosis

miRNAs             Targets      References


miR-145             Bnip3          [72]

miR-199a        Hif-1[alpha],      [89]

miR-21              PDCD4          [83]

miR-328            Atp2a2          [84]

miR-214             NCX1           [87]
                    pten           [92]

miR-24               Bim         [85,86]

miR-146b           RNase L         [91]

miR-378           Caspase-3        [80]

miR-494             PTEN           [73]

miR-499             Drp1           [74]

miR-185             Nhe1           [79]

miR-30 family    [beta]1AR,      [75, 76]

miR-210            Efna3,        [81, 82]



miR-92a           NF-kB p65        [94]

miR-675             VDAC1          [78]

miR-138             Lcn2         [96, 97]

miR-124             STX2           [88]


miR-1               HSP60        [75,102]

miR-200c           GATA-4          [93]

miR-363            Notch1          [90]

miR-122           caspase-8        [99]

miR-181c            Bcl-2          [77]

miR-15              Chek1         [104]

miR-34a             pnuts       [106,107]

miR-378             IGF1R         [100]

miR-27a             IL-10          [95]

miR-29               PIO           [98]

miR-28              PDK1        [101,105]

miR-195             Sirt1         [103]

AIFM3: apoptosis inducing factor; ALDH2: aldehyde dehydrogenase 2;
Bcl-2: B-cell CLL-lymphoma 2; Bim: Bcl2 like 11; Bnip3: Bcl2-
adenovirus E1B 19 kDa interacting protein 3; [beta]1AR: adrenoceptor
[beta]1; [beta]2AR: adrenoceptor [beta] 2; CaMKII[delta]: calcium-
calmodulin-dependent protein kinase II, [delta]; Chek1: checkpoint
kinase 1; CypD: Cyclophilin+D; Drp1: dynamin-related protein-1; Efna3:
ephrin A3; FGFR1: fibroblast growth factor receptor 1; Gi[alpha]2: G
protein a i subunit; Hif-1[alpha]: hypoxia-inducible factor 1, [alpha]
subunit; HSP60: heat shock protein 60; IGF-1R: insulin-like growth
factor 1 receptor; IL-10: interleukin 10; Lcn2: lipocalin-2; LIF:
leukemia inhibitory factor; NCX1: sodium-calcium exchanger 1; Nhe1:
Na+-H+ exchanger 1; PDCD4: programmed cell death 4; PDK1:3-
phosphoinositide-dependent protein kinase-1; PKC[epsilon]: protein
kinase c beta1; PTEN: phosphatase and tensin homolog; Ptp1b: Protein
Tyrosine Phosphatase-1B; P53: tumor protein p53; p65: tumor protein
p65; ROCK1: Rho associated coiled-coil containing protein kinase 1;
SIRT1: Sirtuin 1; SMAD7: SMAD family member 7; DCM: diabetic

Table 4: Summary of reported miRNAs and their targets in Autophagy.

miRNAs           Targets

miRNAs regulate the induction of autophagy

miR-106b          ULKl
miR-25            ULKl
miR-17-5p         ULKl
miR-4487          ULKl
miR-595           ULKl
miR-885-3p        ULK2
miR-26b           ULK2

miRNAs regulate the vesicle nucleation of autophagy

miR-30a         Beclin-1
miR-384-5p      Beclin-1
miR-409-3p      Beclin-1
miR-216a        Beclin-1
miR-630           UVRAG
miR-374a          UVRAG

miRNAs regulate the vesicle elongation and retrieval of autophagy

miR-181a          Atg5

miR-224-3p        Atg5
miR-30a           Atg5
miR-30d           Atg16

miR-375           ATG7
miR-20a           ATG7
miR-137           ATG7
miR-96            ATG7
miR-188-3p        ATG7
miR-199a-5p       ATG7
miR-519A      ATG16, ATG10
miR-376a/b        ATG4C
miR-101           ATG4D
miR-382            LC3
miR-21           LC3-II
MiR-130a          Atg2B
miR-143           Atg2B
miR-34a           Atg9

miRNAs regulate the formation and degradation of autolysosome

miR-502           RAB1B
miR-451           RAB14
miR-207           LAMP2
miR-487-5p        LAMP2
miR-205       RAB27A, LAMP3

miRNAs                        Effector cells (Tissue)

miRNAs regulate the induction of autophagy

miR-106b                      C2C12 (myoblast cells)
miR-25                         MCF-7 (breast cancer)
miR-17-5p                TIB-71 (murine macrophage cells)
miR-4487                      SH-SY5Y (neuroblastoma)
miR-595                       SH-SY5Y (neuroblastoma)
miR-885-3p               JHU-029 (squamous cell carcinoma)
miR-26b                     PC3, C4-2 (prostate cancer)

miRNAs regulate the vesicle nucleation of autophagy

miR-30a         786-0, A489 (renal carcinoma), MG-63 (osteosarcoma)
miR-384-5p                   primary mouse macrophages
miR-409-3p                Lovo Oxa R (colorectal cancer)
miR-216a                     PANC-1 (pancreas cancer)
miR-630                  JHU-029 (squamous cell carcinoma)
miR-374a                 JHU-029 (squamous cell carcinoma)

miRNAs regulate the vesicle elongation and retrieval of autophagy

miR-181a      MCF-7 (breast cancer) Huh7 (liver cancer) K562 (chronic
                               myelogenous leukemia)
miR-224-3p                  U251 and U87 (glioblastoma)
miR-30a                             K562 (CML)
miR-30d         A2780, OVCAR10 and 2008 (ovarian cancer), T47D and
                               MCF-7 (breast cancer)
miR-375                     Huh7, Hep3B (liver cancer)
miR-20a                       SiHa (cervical cancer)
miR-137                         U87 (glioblastoma)
miR-96               LNCaP, 22Rv1, and LAPC4 (prostate cancer)
miR-188-3p                             NMCMs
miR-199a-5p                 Huh7, HepG2 (liver cancer)
miR-519A                 JHU-029 (squamous cell carcinoma)
miR-376a/b           MCF-7 (breast cancer) Huh7 (liver cancer)
miR-101                        MCF-7 (breast cancer)
miR-382                        renal mesangial cells
miR-21                        diabetic mesangial cell
MiR-130a                         MEC-1 (leukemia)
miR-143                         H1299 (lung cancer)
miR-34a                                NMCMs

miRNAs regulate the formation and degradation of autolysosome

miR-502                     HCT116 (colorectal cancer)
miR-451              A549, SPC-A1, and NCI-H520 (lung cancer)
miR-207                   primary cortical neuronal cells
miR-487-5p                   A549, H1299 (lung cancer)
miR-205                    DU145, PC3 (prostate cancer)

miRNAs        References

miRNAs regulate the induction of autophagy

miR-106b        [108]
miR-25          [109]
miR-17-5p       [110]
miR-4487         [17]
miR-595          [17]
miR-885-3p      [111]
miR-26b         [112]

miRNAs regulate the vesicle nucleation of autophagy

miR-30a       [113,114]
miR-384-5p      [115]
miR-409-3p      [116]
miR-216a        [117]
miR-630         [118]
miR-374a        [118]

miRNAs regulate the vesicle elongation and retrieval of autophagy

miR-181a        [119]

miR-224-3p      [120]
miR-30a         [121]
miR-30d         [122]

miR-375         [123]
miR-20a         [124]
miR-137         [125]
miR-96           [32]
miR-188-3p      [126]
miR-199a-5p     [127]
miR-519A        [118]
miR-376a/b    [128,129]
miR-101         [130]
miR-382         [131]
miR-21          [132]
MiR-130a        [133]
miR-143         [134]
miR-34a         [135]

miRNAs regulate the formation and degradation of autolysosome

miR-502         [136]
miR-451         [137]
miR-207         [138]
miR-487-5p      [139]
miR-205         [140]

AMPK: adenosine 5'-monophosphate-(AMP-) activated protein kinase;
mTOR: mammalian target of rapamycin; ATG: AuTophaGy; UVRAG: UV
radiation resistance associated gene; VSP: venom serine protease;
LAMP2: lysosomal associated membrane protein 2; NMCMs: neonatal mouse
cardiomyocytes; RAB1B: member RAS oncogene family; RAB14: member RAS
oncogene family; RAB27A: member RAS oncogene family; LAMP3: lysosomal
associated membrane protein 3.

Table 5: Summary of reported miRNAs and their targets in Inflammatory

miRNAs               Targets                 Regulation factors

MiR-155       SOCS1, SHIP1, IL-13Ra1         IFN-b, TNF-a, IL-1
miR-125a          TNFAIP3 (A20)                     LPS
miR-125b          TNFAIP3, TNF-a                    LPS
miR-125a-5p         TLR2, TLR4                      LPS
miR-21                CSF-1R                        LPS
miR-22             Rasa1, Nfat5                    PPARg
miR-27a               PPARg                        M-CSF
Mir-375                PDK1                        M-CSF
MiR-126               ADAM9                         LPS
MiR-145-5p             CD40            IL-1[beta], TNF-[alpha], IL-6
MiR-146a           IRAK, TRAF6                LPS, TNF-[alpha]

miRNAs        References

MiR-155       [141-146]
miR-125a        [147]
miR-125b      [123,147]
miR-125a-5p     [148]
miR-21          [149]
miR-22          [150]
miR-27a         [151]
Mir-375         [152]
MiR-126         [153]
MiR-145-5p      [154]
MiR-146a        [155]

SOCS1: suppressor of cytokine signaling 1; SHIP1: inositol
polyphosphate-5-phosphatase D; TNF-a: tumor necrosis factor a;LPS:
lipopolysaccharides; CSF-1R: colony stimulating factor 1 receptor;
Rasa1: RAS p21 protein activator 1; Nfat5: nuclear factor of activated
T-cells 5; PDK1: pyruvate dehydrogenase kinase 1; IRAK: interleukin 1
receptor associated kinase; TRAF6: TNF receptor associated factor 6;
ADAM9: A disintegrin and metalloproteinase 9.

Table 6: Summary of reported miRNAs and their targets in angiogenesis.

miRNAs            Targets               Effector cells


miR-126           Spred-1                   HEPCs
                  PIK3R2                    HEPCs
                   CCN1                     HEPCs

miR-130a            GAX                HUVECs and EGM-2
                   HOXA5               HUVECs and EGM-2
                   PTEN                    MI mouse

miR-17-92          Tsp1                     HUVECs
cluster            CTGF                     HUVECs
                   BMP4                     HUVECs

miR-210         Ephrin-A3,                  HUVECs
                   PTP1b                   MHL-1Cs

miR-146a           VEGF                     hMSCs

miR-296             HGS                    HBMVECs

miR-378            SuFu                   U87 cells
                   Fus-1                  U87 cells

miR-132         p120RasGAP                  HUVECs

miR-23/27        Sprouty2,                  HUVECs
                  Sema6A                    HUVECs

miR-27b            Dll4,                LLC1 and ATCC
                PPAR[gamma]             LLC1 and ATCC

miR-24            GATA2,              HVSMCs and HUVECs
                   PAK4               HVSMCs and HUVECs
                   eNOS          MI mouse, HUVECs and HMVECs


miR-214            XBP1                     HUVECs

miR-34 family      SIRT1           HUVECs, HMVECs and HAECs
                 vinculin     LNA-antimiR-34-treated MI mice and
                                          H9c2 cell
                  Pofut1      LNA-antimiR-34-treated MI mice and
                                          H9c2 cell
                  Notch1      LNA-antimiR-34-treated MI mice and
                                          H9c2 cell
                   VEGF       LNA-antimiR-34-treated MI mice and
                                          H9c2 cell
                  Sema4b      LNA-antimiR-34-treated MI mice and
                                          H9c2 cell

miR-29a/101a      TGFb-1                   MI rats

miR-15b-5p         AKT3                     HUVECs

miR-100            mTOR                  ESMCs, VSMCs

miR-200b         ZEB1/SIP1             MDCKCs and HBCCs
                   GATA2            Dermal wound-edge ECs
                  VEGFR2            Dermal wound-edge ECs
                   Flt1                     HUVECs
                    KDR                     HUVECs

miR-503           cdc25A          HUVECs, HMVECs and HVSMCs
                   CCNE1          HUVECs, HMVECs and HVSMCs

miR-15a            FGF2                     HUVECs
                   VEGF                     HUVECs

miR-320            IGF-1                 MCECs, NRCMs
                   Hsp20                 MCECs, NRCMs
                   Ets2                  MCECs, NRCMs

miR-329            CD146                HUVECs, HMECs

miR-92a            ITGA5           RMUG-S, OVISE and RMG-1

miRNAs            Targets       Signal pathways       References


miR-126           Spred-1             VEGF            [156,157]
                  PIK3R2              VEGF
                   CCN1             TEN/AKT

miR-130a            GAX          Transcription        [158,159]
                   HOXA5         Transcription
                   PTEN             PI3K/Akt

miR-17-92          Tsp1               VEGF              [160]
cluster            CTGF            TGF[beta]
                   BMP4            Bmp4/Smad

miR-210         Ephrin-A3,            VEGF           [81,161,162]
                   PTP1b              VEGF

miR-146a           VEGF               Shh                [65]

miR-296             HGS                                 [163]

miR-378            SuFu               Shh             [164,165]
                   Fus-1              Shh

miR-132         p120RasGAP            Ras               [166]

miR-23/27        Sprouty2,          ERK-MAPK            [167]
                  Sema6A              VECF

miR-27b            Dll4,           Dll4/Notch           [168]
                PPAR[gamma]           PPAR

miR-24            GATA2,            cGMP-PKG          [169, 170]
                   PAK4        TGF-[beta]1/Smads
                   eNOS             PI3K/Akt


miR-214            XBP1               VEGF              [171]

miR-34 family      SIRT1              AMPK            [172-174]
                 vinculin             FAK1

                  Pofut1             Notch

                  Notch1             Notch

                   VEGF               VEGF

                  Sema4b              VECF

miR-29a/101a      TGFb-1          TGFb pathway          [175]

miR-15b-5p         AKT3             PI3K-Akt            [176]

miR-100            mTOR               mTOR              [177]

miR-200b         ZEB1/SIP1            mTOR            [178-181]
                   GATA2              VEGF
                  VEGFR2              VEGF
                   Flt1               VEGF
                    KDR               VEGF

miR-503           cdc25A              MAPK              [182]
                   CCNE1             Notch

miR-15a            FGF2             PI3K-AKT          [183,184]
                   VEGF               VEGF

miR-320            IGF-1            PI3K-Akt          [185,186]
                   Hsp20        RNA degradation
                   Ets2             PI3K-Akt

miR-329            CD146      VEGF and TNF-[alpha]      [187]

miR-92a            ITGA5            Rho/ROCK          [188-190]

CCNE1: cyclin E1; cdc25A: cell division cycle 25A; CTGF: connective
tissue growth factor; Dll4: delta-like protein 4; eNOS: endothelial
nitric oxide synthase; Ets2: Euro Truck Simulator 2; FGF2: fibroblast
growth factor 2; FGFR1: fibroblast growth factor receptor 1; GATA2:
GATA binding protein 2; GAX: gaseous oxygen; HGS: hepatocyte growth
factor-regulated tyrosine kinase substrate; HOXA5: homeobox A5; IGF-
1: insulin-like growth factor 1; ITGA5: integrin subunits a5; mTOR:
mechanistic target of rapamycin; PIK3R2: phosphoinositol-3 kinase
regulatory subunit 2; Pofut1: protein O-fucosyltransferase 1;
Ppar[gamma]: peroxisome proliferator-activated receptor [gamma]; PTEN:
phosphatase and tensin homolog; Sema4b: semaphorin 4B; Sema6A:
semaphorin 6A; SIP1: Smad interacting protein 1; SIRT1: Sirtuin 1;
Sprouty2: sprouty homolog 2; Tsp1: thrombospondin-1; VEGF: vascular
endothelial growth factor; VEGFR2: vascular endothelial growth factor
receptor 1; XBP1: X-box binding protein 1; ZEB1: zinc finger E-box-
binding homeobox 1; FAK: focal adhesion kinase; HUVECs: human
umbilical vein ECs; EGM-2: endothelial growth medium 2; MHL-1Cs: mouse
HL-1 cardiomyocytes; hMSCs: human mesenchymal stem cells; Shh: sonic
hedgehog signaling; HBMVECs: human brain microvascular endothelial
cells; LLC1: Lewis lung carcinoma; ATCC: RAW 264.7 mouse macrophage
cell lines; HVSMCs: human vascular smooth muscle cells; HUVECs: human
umbilical vein endothelial cells; HMVECs: human microvascular ECs;
HAECs: human aortic endothelial cell; ESMCs: endothelial smooth muscle
cells; VSMCs: vascular smooth muscle cells; HVSMCs: human VSMCs cells;
MDCKCs: Madin-Darby canine kidney cells; HBCCs: human breast cancer
cells; dermal wound-edge ECs: dermal wound-edge endothelial cells;
MCECs: mouse cardiac endothelial cells; NRCMs: neonatal rat
cardiomyocytes; HMECs: human microvascular endothelial cells.
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Author:Chen, Chao; Ponnusamy, Murugavel; Liu, Cuiyun; Gao, Jinning; Wang, Kun; Li, Peifeng
Publication:BioMed Research International
Article Type:Report
Date:Jan 1, 2017
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