MicroRNA as a Therapeutic Target in Cardiac Remodeling.
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 . 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 . 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 . 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 . 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) . 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 . MiR-10a  and miR-497  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+] . MiR-455 is an important miR in the developing heart that targets calreticulin to prevent pressure overload induced hypertrophy . 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 . MiR-212/132 family  and miR-23a  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 .
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 . 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 . 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 . 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 , while miR-17-3p targets metallopeptidase inhibitor 3 (TIMP3), a negative regulator of PTEN-Akt pathway, and resulting in cardiomyocyte hypertrophy . MiR-21 targets suppressors of hypertrophic response by inhibiting translation of SH3 domain-containing protein 2 (SORBS2), PDZ, and LIM domain 5 (PDLIM5) . 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 . 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 .
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 . 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. . 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 . 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 . Similarly, antagonist of miR-101 attenuates experimental cardiac hypertrophy by target the expression of ras-related protein-1A (Rab1A) . The antimir of miR-208a attenuates cardiac remodeling by upregulation of expression Myh7 in pressure overload induced heart failure in rats . 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 . 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 . 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 . 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 . 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 . 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 .
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 . 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 . A recent study found that miR29 acts as an antifibrotic factor by accelerating the expression of multiple extracellular matrix genes including elastin , 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 . MiR-146a targets VEGF expression and suppresses VEGF dependent proliferation and expansion myofibroblasts . 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 . 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 . 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 . 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 . 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]) . miR-499 also inhibits mitochondrial pathway of cell death by abolishing calcineurin-mediated dephosphorylation of dynamin-related protein-1 (Drp1) and reducing mitochondrial fission . 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 . 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 . 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 . 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 .
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) . The upregulation of miR-378 enhances cell survival by inhibiting caspase-3 expression in cardiomyocytes during ischemia reperfusion injury . 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  and miR-328  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  and upregulation of miR-24 decreases apoptosis and necrosis in ischemic myocytes by inhibiting BCL2L11 gene . 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 . 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 .
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] . miR-363 controls hypoxia inducible cardiac apoptosis via regulation of Notch1 expression and its downstream signaling . 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 . 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 . 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 , while inhibition of hypoxia induced increase of miR-92a promotes translation of SMAD7 and blocking NF-kB p65 signaling . 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 . miR-122 promotes cardiac apoptosis by inhibiting blockers of caspase-8 and enhancing its expression . 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) . 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 , 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 . MiR-195 also downregulates Bcl-2 and Sirt1, which subsequently leads to overproduction of ROS to induce cell death in cardiomyocytes . 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) , which causes cell cycle arrest and subsequently cell death. miR-28  and miR-34a  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 . 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 . 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 . Experimental studies have shown that miR-25 , miR-17-5p , miR-4487, and miR-595  can directly target ULK1, while miR-8853p  and miR-26b  block autophagy initiation by inhibiting ULK2 . 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 , whereas miR-181a , miR-30a , and miR-224-3p  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 . miR-519A has the capability to suppress expression of both Atg16 and Atg10 . 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 . Wang et al.  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 .
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 . 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 . 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 . 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 . 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 . 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 . miR-155 also promotes macrophage survival by upregulating the SHIP1-Akt signaling cascade . 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 . 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 . Similarly, miR-155 can block the activity of macrophages by directly targeting proinflammatory NF-[kappa]B signaling transcription factor in atherosclerotic plaque . 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 . PPAR[gamma] promotes alternative activation and polarization of macrophage (M2) by enhancing the expression of miR-22, which targets Rasa1 and Nfat5 . However, miR-27a switches on M1 macrophage polarization by blocking PPAR[gamma] . mir-375 promotes inflammation induced cardiomyocyte cell death by inhibiting PDK1-Akt signaling and increasing proinflammatory cytokines .
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 . 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 . Interestingly, miR-125b has been reported to suppress the activity and stability of TNF-[alpha] transcript and thereby it reduces inflammatory responses . 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 . 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 . 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 .
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 . 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 . 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] . Bauernfeind et al. found that miR-223 negatively regulates NLRP3 inflammasome activity and this inhibition could block the initiation of pyroptosis . 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 . 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 . 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 . The miRNAs such as miR-494 and miR-126-5p act as proangiogenic factors by targeting bone morphogenetic protein 4 (BMP4) , 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 . miR-146a promotes angiogenesis by increasing the expression of VEGF and reducing the fibrotic process at injury site .
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 . 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 . In addition, increased level of miR-378 expression stimulates endothelial cell angiogenic activity . 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 . miR-23 and miR27 promote angiogenesis by inhibiting two antiangiogenic factors such as Sprouty2 and Sema6A proteins , while miR-27b expression accelerates angiogenesis by regulating translation of Dll4/Notch axis, PPAR[gamma] and its downstream effectors . 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 . In response to stress, the upregulation of miR-34 family members (miR-34a, miR-34b, and miR-34c) , 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) . By targeting the proangiogenesis TGFb-1, miR-29a and miR-101a inhibit TGF[beta] pathway in endothelial cells in MI rats . Overexpression of miR-15b-5p suppresses arteriogenesis and angiogenesis in mice by directly targeting protein kinase B-3 (AKT3) . 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 . 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 . 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 . 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 . miR-329 abrogates angiogenesis by targeting CD146, an endothelial adhesion molecule required to maintain endothelial cell integrity . 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 . The known miRNAs involved in angiogenesis and their target genes are summarized in Figure 6 and Table 6.
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; email@example.com and Peifeng Li; firstname.lastname@example.org
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 hypertrophy. miRNAs Targets Effector cells Antihypertrophic 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 Prohypertrophic 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 Antihypertrophic 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  miR-497 Sirt4 AMPK  miR-133 AT1R ERK-MAPK [13,14] Cdc42, MAPK Rho-A, cGMP-PKG Nelf-A/WHSC2 Transcription miR-223 TNNI3K Calcium signaling  miR-455 CRT Calcium signaling  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  miR-21-3p SORBS2 Transcription  PDZ Transcription PDLIM5 Transcription miR-208 AT1R ERK-MAPK [27, 28, 44] THRAP1 Thyroid hormone Myh7 miR-124 Grp78 Reticulum (ER) stress  signaling CRT Calcium signaling miR-297 Sig-1R ER stress signaling  miR-17-3p TIMP3 PTEN-AKT pathway  miR-155 Mef2A Calcineurin pathway [23, 33] Jarid2 Calcineurin pathway AGTR1 Calcium signaling pathways miR-212/132 Foxo3 PI3K-Akt  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  Murf1 PKC miR-27b Ppar[gamma] PPAR  miR-328 Serca2a cGMP-PKG  miR-185 Camk2d Calcium  Ncx1 cGMP-PKG  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 fibrosis. miRNAs Targets Effector cells Antifibrosis 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 JNK1 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 Profibrosis 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 Antifibrosis 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 pathway 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 Profibrosis 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 Antifibrosis miR-101a TGF-[beta]R1, [47, 48] c-Fos miR-133/30 ctgf  miR-24 Furin  Elastin [61-63] Fbn1 miR-29 Coll[alpha]l Col1[alpha]2 Col3[alpha]1, FBN, miR-146a VEGF  miR-98 TGF[beta]R1  miR-433 AZIN1  JNK1 miR-142-3p HMGB1  miR-29b Tgf[beta]1,  miR-19a-3p/19b-3p TGF[beta] RII  miR-22 Smad4  miR-378 TGF-[beta]1  miR-26a COL1,  CTGF TGF-[beta]R1 [53, 54] miR-15 family p38 SMAD3 SMAD7 Endoglin Profibrosis miR-21 Spry1 [56, 57] TGF[beta]RIII Endoglin [28, 68, 69] miR-208a b-MHC THRAP1 Akt  MAPKs Egr1 miR-499 Egr2 Fos Myh7 Acta1 miR-122 TGF-[beta]1  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 apoptosis. miRNAs Targets Effector cells Antiapoptosis 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 NRCMs NRCMs 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 Proapoptosis 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 Antiapoptosis 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 [beta]2AR, Gi[alpha]2, [beta]-adrenergic pathway P53 Drp1 [beta]-adrenergic pathway p53 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 Proapoptosis 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 Antiapoptosis miR-145 Bnip3  miR-199a Hif-1[alpha],  Sirt1 miR-21 PDCD4  miR-328 Atp2a2  miR-214 NCX1  pten  miR-24 Bim [85,86] miR-146b RNase L  miR-378 Caspase-3  miR-494 PTEN  ROCK1 CaMKII[delta] FGFR2 LIF miR-499 Drp1  miR-185 Nhe1  miR-30 family [beta]1AR, [75, 76] [beta]2AR, Gi[alpha]2, P53 Drp1 miR-210 Efna3, [81, 82] Ptp1b AIFM3 miR-92a NF-kB p65  miR-675 VDAC1  miR-138 Lcn2 [96, 97] miR-124 STX2  Proapoptosis miR-1 HSP60 [75,102] Bcl-2 PKC[epsilon] miR-200c GATA-4  miR-363 Notch1  miR-122 caspase-8  miR-181c Bcl-2  miR-15 Chek1  miR-34a pnuts [106,107] ALDH2 miR-378 IGF1R  miR-27a IL-10  miR-29 PIO  miR-28 PDK1 [101,105] ALDH2 miR-195 Sirt1  Bcl-2 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 cardiomyopathy. 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  miR-25  miR-17-5p  miR-4487  miR-595  miR-885-3p  miR-26b  miRNAs regulate the vesicle nucleation of autophagy miR-30a [113,114] miR-384-5p  miR-409-3p  miR-216a  miR-630  miR-374a  miRNAs regulate the vesicle elongation and retrieval of autophagy miR-181a  miR-224-3p  miR-30a  miR-30d  miR-375  miR-20a  miR-137  miR-96  miR-188-3p  miR-199a-5p  miR-519A  miR-376a/b [128,129] miR-101  miR-382  miR-21  MiR-130a  miR-143  miR-34a  miRNAs regulate the formation and degradation of autolysosome miR-502  miR-451  miR-207  miR-487-5p  miR-205  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 Response. 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  miR-125b [123,147] miR-125a-5p  miR-21  miR-22  miR-27a  Mir-375  MiR-126  MiR-145-5p  MiR-146a  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 Proangiogenesis 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 Antiangiogenesis 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 Proangiogenesis 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  cluster CTGF TGF[beta] BMP4 Bmp4/Smad miR-210 Ephrin-A3, VEGF [81,161,162] PTP1b VEGF miR-146a VEGF Shh  miR-296 HGS  miR-378 SuFu Shh [164,165] Fus-1 Shh miR-132 p120RasGAP Ras  miR-23/27 Sprouty2, ERK-MAPK  Sema6A VECF miR-27b Dll4, Dll4/Notch  PPAR[gamma] PPAR miR-24 GATA2, cGMP-PKG [169, 170] PAK4 TGF-[beta]1/Smads eNOS PI3K/Akt Antiangiogenesis miR-214 XBP1 VEGF  miR-34 family SIRT1 AMPK [172-174] vinculin FAK1 Pofut1 Notch Notch1 Notch VEGF VEGF Sema4b VECF miR-29a/101a TGFb-1 TGFb pathway  miR-15b-5p AKT3 PI3K-Akt  miR-100 mTOR mTOR  miR-200b ZEB1/SIP1 mTOR [178-181] GATA2 VEGF VEGFR2 VEGF Flt1 VEGF KDR VEGF miR-503 cdc25A MAPK  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]  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|
|Date:||Jan 1, 2017|
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