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Regulation of Sirtuin-Mediated Protein Deacetylation by Cardioprotective Phytochemicals.

1. Introduction

Cardiovascular diseases (CVDs) have remained the leading cause of death worldwide for the past two decades. In 2012, coronary artery disease alone was responsible for 7.4 million deaths, and CVDs accounted for 17.3 million deaths worldwide [1]. Based on current estimates, the number of CVD-related deaths is expected to increase to 23.6 million by 2030 [1]. Coronary heart disease, hypertension, peripheral vascular disease, myocardial infarctions, strokes, and heart failure are the most prevalent CVDs [2]. Their aetiology is diverse and includes various risk factors, such as aging, obesity, smoking, and diabetes [1]. Abundant natural biologically active substances, also known as functional molecules, from diverse sources can potentially decrease risk factors for CVDs, thereby significantly reducing the incidence of CVDs [3-7].

The search for new functional molecules to prevent CVDs faces a major challenge due to the growing list of pathogenic mechanisms attributed to a multitude of interrelated pathways. Research on the role of posttranslational modifications (PTMs) in the development and progression of CVDs has spiked dramatically, with modulation of PTMs currently considered a potential therapeutic strategy [8-10].

PTMs are important regulators of the synthesis, subcellular localization, and enzymatic activity of proteins. PTMs also modulate signal transduction pathways and cellular metabolism (reviewed in [11]). PTMs respond rapidly to both internal and external (environmental) stimulation, allowing for efficient signal transmission and amplification. Among PTMs, most research thus far has focused on protein phosphorylation, although protein acetylation has emerged as a key regulatory mechanism and an attractive therapeutic target in the field of chronic diseases ([8-10], reviewed in [12]). Although acetylation was first described in the early 1960s, detailed studies of its biological role did not take place until the late 1990s. The first description of protein acetylation focused on histones as targets of histone acetyltransferases, which transfer acetyl groups from acetyl coenzyme A to specific lysine residues on histones, exposing DNA to transcription [13]. Conversely, histone deacetylases (HDACs) remove acetyl groups from acetylated lysine amino acids on histones, allowing chromatin condensation and therefore silencing of gene transcription [13]. Later research described the deacetylation of histone and nonhistone proteins, orchestrated by a subgroup of deacetylases known as sirtuins [14]. A classification system of HDACs was later developed based on their molecular targets and mechanism of action. Briefly, there are four classes of HDACs in mammals, all of which utilize zinc as a cofactor, except for sirtuins (class III), which utilize nicotinamide dinucleotide ([NAD.sup.+]) as a substrate in enzymatic activity [14, 15]. As [NAD.sup.+] levels vary according to nutrient availability, the activity of sirtuins is strongly associated with the metabolic status of the cell, with their activity increasing under conditions of calorie restriction and exercise [15-17].

Sirtuins are widely distributed in prokaryotic and eukaryotic species, with seven isoforms characterized in humans [18, 19]. They share a common catalytic domain but differ with regard to their N- and C-terminal sequences, which determine their susceptibility to regulation by sirtuin-activating compounds [20] and PTMs (reviewed in [21]). The molecular targets and subcellular localization of different sirtuins vary, with some sirtuins present in more than one organelle. Although all sirtuins are classified as deacetylases, Sirt4 and Sirt5 have weak deacetylase activity and function as demalonylases and deacylases [22, 23] (Figure 1).

2. Protein Acetylation and CVDs

Research on the impact of protein acetylation in CVDs has focused mainly on Sirt1, Sirt3, and Sirt6, with little information regarding the function of the remaining sirtuins. Sirt1 and Sirt3 are involved in the regulation of important cellular mechanisms (e.g., apoptosis and cell survival), as well as the regulation of reactive oxygen species levels, hypertrophic and fibrotic responses, and mitochondrial biogenesis and function (Figure 2). Recent evidence suggests that impairments in the sirtuin family are associated with the development and progression of CVDs, as discussed below. Sirt1 modulates early embryogenesis, and homozygous [sirt1.sup.-/-]-mice die shortly after birth [43]. As shown in deletion studies of crossbred mice, [sirt1.sup.-/+] mice develop dilated cardiomyopathy [44] and exhibit increased cardiac injury induced by ischemia/reperfusion (I/R) [45]. These deleterious effects are associated with inhibition of Sirt1-mediated activation of forkhead box protein O1 (FOXO1) and O3 (FOXO3), which are responsible for the transcription of antioxidant enzymes, such as superoxide dismutase and catalases [44-46]. Sirt1 deficiency results in activation of proliferative and proinflammatory pathways involving tumour necrosis factor-a and nuclear factor-[kappa]B (NF-[kappa]B), leading to cardiac hypertrophy, fibrosis, and heart failure [24, 45] (Figure 2). With aging, the deleterious effects of Sirt1 deficiency become more prominent [47, 48]. Sirt1 stimulation and overexpression appears to provide protection against age-related cardiac diseases [48-50]. In addition, low to moderate overexpression of Sirt1 (2.5-7.5 times) mitigates cardiac hypertrophy induced by aging [48], provides protection against oxidative stress-induced cardiotoxicity [45], and improves endothelial function [26, 51]. Sirt1 stimulation and overexpression also has a range of other beneficial effects (Table 1). Sirt1 expression increases (12-fold) in hearts of dogs with experimental heart failure induced by rapid pacing [55]. Transgenic mice with cardiac-specific overexpression (20-fold) of Sirt1 exhibit mitochondrial dysfunction and dilated cardiomyopathy [64]. Thus, it appears that moderate stimulation of Sirt1 is beneficial for cardiac function, whereas excessive stimulation has deleterious effects on the heart.

Sirt3 regulates mitochondrial protein acetylation, and severe hyperacetylation of mitochondrial proteins occurs in [sirt3.sup.-/-] knockout mice [29]. Such hyperacetylation has direct implications for ATP-dependent cellular processes, as hyperacetylation of enzymes involved in the Krebs cycle and electron transport chain translates into severe depletion of ATP (as much as 50%) [30], as well as compromised cardiac myocyte function. As demonstrated in previous studies, [sirt3.sup.-/-] mice develop cardiac hypertrophy, fibrosis, and mitochondrial dysfunction in an age-dependent manner [31]. In addition, [sirt3.sup.-/-] mice are more sensitive to damage induced by I/R injury [32-35] and microvascular dysfunction [34]. In contrast, overexpression of Sirt3 in mice hearts provides protection against cardiac hypertrophy and fibrosis [36,37]. It also provides protection against oxidative stress-induced damage and apoptosis in the myocardium [38]. These protective effects are associated with activation of the antioxidant defence response, mediated by FoxO3a, which preserves mitochondrial energy production via the activation of mitochondrial dehydrogenases, thereby preventing mitochondrial permeability transition pore (mPTP) opening [38]. mPTP opening is followed by increases in [Ca.sup.2+] overload, in addition to depletion of ATP and mitochondrial swelling, which eventually cause necrosis and apoptosis in cardiac myocytes [65]. In animal models of metabolic syndrome and ventricular dysfunction, mitochondria are prone to mPTP opening as compared with controls, concomitant with decreased Sirt3 expression and a hyperacetylated mitochondrial profile [66]. In biopsies of patients with heart failure, Sirt3 expression was lower in obese patients than in nonobese patients. Interestingly, acetylation profiles of patients with end-stage heart failure are correlated with body mass index and cardiac remodelling [66].

As shown in similar studies, the level of protein acetylation is closely associated with the metabolic status of the cell, and it varies with nutritional status [33]. Moreover, persistent hyperacetylation in the heart, as occurs in Sirt3 knockout mice, results in increased sensitivity to hemodynamic stress [67]. In addition, an increase in the NADH:NAD ratio inhibits Sirt3, resulting in mitochondrial hyperacetylation [67]. Restoring Sirt3 activity via normalization of the NADH/NAD ratio reverses protein hyperacetylation in complex I-deficient hearts, as well as in hearts with cardiac remodelling. Thousands of mitochondrial acetylation sites have been identified in acetylome analyses of [sirt3.sup.-/-] mice [68] and human failing hearts [8]. Among these, hyperacetylation of the malate-aspartate shuttle and regulators of mPTP opening are linked to the development of cardiac dysfunction [68]. Significant mitochondrial lysine hyperacetylation occurs in humans with end-stage heart failure, as shown by a myocardial acetylproteomic study [8].

Of note, homozygous [sirt3.sup.-/-] mice do not express any specific phenotype at birth, with cardiac development and function appearing normal under physiological conditions. Nevertheless, when exposed to I/R injury or agonist-induced cardiac hypertrophy, [sirt3.sup.-/-] mice exhibit severe mitochondrial hyperacetylation, in addition to decreased mitochondrial and myocardial function and lower survival rates [30]. This highlights the role of Sirt3 in the maladaptation observed during stressful cardiac conditions [35] and suggests that an NAD precursor, as well as sirtuin-activating compounds (STACs), could be used as cardiac therapy.

Sirt6 is a negative regulator of the insulin-like growth factor-1-protein kinase B pathway, which is implicated in the development of heart failure. Although [sirt6.sup.-/-] mice develop cardiac hypertrophy and heart failure, transgenic mice overexpressing this sirtuin are protected against both events. Likewise, Sirt6 expression levels are reduced in patients with failing hearts and in those with atherosclerosis [25,69]. Sirt6 expression levels are also decreased in murine models [25]. Notably, [sirt6.sup.-/-] deficiency is associated with overexpression of proinflammatory cytokines, such as tumour necrosis factor superfamily member 4 and vascular cell adhesion molecule 1. These findings suggest that maintaining Sirt6 expression might be a novel therapeutic strategy against both cardiac and vascular dysfunction. Figure 2 summarizes the main reported targets and physiological roles of sirtuins in CVD prevention.

3. Regulation by Phenolic Compounds and Synthetic Molecules of Protein Acetylation in CVDs

The potential roles of several molecules as sirtuin activators have been studied due to their cardioprotective effects, which have been described both in vitro and in vivo (Figure 3). Most of these molecules are phenolic compounds, such as resveratrol (trans-3,5,4'-trihydroxystilbene) [17], but some synthetic molecules have been developed and successfully tested [20]. As phenolic compounds are hydrophobic, they can permeate the cell membrane to perform biological functions. The rate at which they enter the cell depends on both the size of the molecule and hydrophobicity of the attached functional groups [27,70].

The mechanism by which phenolic molecules promote the activity of sirtuins, specifically that of Sirt1, may involve allosteric activation and direct binding to a negatively charged amino acid from the N terminus, [54]. The binding of STACs lowers the Km of the substrate and thus enhances enzymatic activity. Although sirtuins share a common catalytic domain, they differ in their N- and C-terminal sequences. Thus, the mechanism by which phenolic molecules promote the activity of Sirt1 cannot be generalized to other sirtuin isoforms. As shown in previous research, activators of other sirtuins, such as Sirt3, directly interact with the protein, but the specific mechanism remains unclear [37]. Targeting adenosine monophosphate protein kinases (AMPKs) upregulates both Sirt1 activity and that of the peroxisome proliferator-activated receptor gamma coactivator 1-[alpha] (PGC1-[alpha]), a transcriptional coactivator, thereby indirectly increasing nuclear and mitochondrial sirtuin activity [28]. Other approaches for Sirt activation involve [NAD.sup.+] precursors, such as nicotinamide riboside or nicotinamide mononucleotide [71], and augmentation of [NAD.sup.+] availability via inhibition of glycohydrolases CD38 and CD157, which convert [NAD.sup.+] to nicotinamide mononucleotide [72]. Detailed descriptions of the mechanism underlying the actions of STACs and the role of sirtuins in CVDs can be found elsewhere [73,74]. The following sections provide a comprehensive review of natural STACs that regulate protein acetylation in CVDs.

3.1. Resveratrol. Resveratrol is a polyphenol found in grapes and red wine. It is one of the best studied phytochemicals, and it is known to provide protection against CVDs. It was first described as a Sirt1 activator by Howitz et al., who demonstrated that resveratrol was capable of reducing the Km of both the acetylated target of Sirt1 and that of [NAD.sup.+] (35- and 5-fold, resp.) [17]. The mechanism underlying the activity of resveratrol was later questioned, with some proposing that it was dependent on the fluorophore utilized to label the evaluated peptide [75]. However, later research confirmed that resveratrol was an allosteric activator of Sirt1 [54].

Resveratrol has been evaluated in different models of cardiac disease, including chronic conditions such as heart failure and atherosclerosis, or damage associated with acute events, such as I/R (Table 1). In vitro, resveratrol decreases oxidative stress, inhibits hypertrophy, promotes cell survival, and inhibits apoptosis [38, 52, 56, 59, 60, 62, 76]. In vivo, supplementation with resveratrol decreases hypertrophy and fibrosis [52]. It also preserves cardiac function in models of heart failure induced by norepinephrine [60], doxorubicin [56-58], steptozotocin [61], and angiotensin II [53]. Furthermore, resveratrol prevents cardiac dysfunction in models of acute myocardial infarction induced by left coronary flow occlusion [76]. These cardioprotective effects are dependent on the activation of Sirt1 [52,56,59,60,62,76] and Sirt3 [38, 53], as both gene silencing and specific sirtuin antagonists block the beneficial response. Moreover, in models of atherosclerosis, such as the apolipoprotein E ([apoE.sup.-/-]) mouse, resveratrol reverses endothelial nitric oxide synthase (eNOS) uncoupling and reduces oxidative stress. As resveratrol also enhances the activity of FoxO, the underlying mechanism possibly involves FoxO via NAD-dependent deacetylation, which contributes to cellular stress resistance [39]. Although sirtuin expression has not been studied in this model, treatment with sirtinol, a sirtuin inhibitor, abolished the beneficial effects of resveratrol supplementation [63].

The decrease in the activity of sirtuins with age is well known. Therefore, several models have studied the effects of supplementation with resveratrol on cardiac disease in a senescence setting. In senescence-accelerated mice, supplementation with resveratrol resulted in the recovery of Sirt1 activity [40]. Resveratrol supplementation also provided protection against hypertrophy and apoptosis, as well as preservation of left ventricular function, as compared with hearts from unsupplemented aged mice [40]. The addition of resveratrol to an exercise regime in aged rats potentiated the increase in Sirt1 activity achieved by exercise alone, and this translated into decreased fibrosis, apoptosis, and improved fractional shortening [41]. The molecular pathways involved in these in vitro and in vivo studies are summarized in Table 1.

3.2. Curcumin. Curcumin (diferuloylmethane), a polyphenol derived from the turmeric plant, is the second most well-studied phenolic compound for the treatment of CVDs. It modulates cardiac acetylation, mainly via the stimulation of Sirt1 [42, 77-79] and inhibition of histone acetyltransferase p-300 (p-300-HAT) [80-84].

The potential of curcumin-induced activation of Sirt1 as a mechanism to improve vascular function was studied in human THP-1-machrophage-derived foam cells [77]. Curcumin activated Sirt1 and decreased cellular cholesterol levels, preventing the formation of atherosclerotic plaques [77]. The authors attributed their findings to Sirt1-dependent activation of the ATP binding transporter cassette 1, which increased cholesterol efflux [77]. Another study showed that curcumin improved vascular function by Sirt1-dependent activation of eNOS [79]. By deacetylating eNOS, Sirt1 stimulated endothelium-dependent NO synthesis and protected endothelial cells against premature senescence induced by oxidative stress [79].

Curcumin-induced inhibition of p300-HAT is associated with decreased acetylation, which provides protection against cardiac injury. In murine models of myocardial infraction, curcumin-induced inhibition of p300-HAT resulted in decreased infract sizes, in addition to the prevention of cardiac hypertrophy and fibrosis and preservation of ventricular function [42,80,81]. The beneficial effects of curcumin have been attributed to is downregulation of transcription factors, such as NF-[kappa]B, GATA binding protein 4, and transforming growth factor [beta]1, that are normally activated in the presence of myocardial damage (Table 2). In models of both chronic and acute myocardial damage, curcumin-induced inhibition of p-300-HAT result in decreased apoptosis in response to deacetylation of p53, as well as inhibition of proapoptotic Bax and caspase 3 [42,80]. These cardioprotective effects were attributed to Sirt1 stimulation [77,79]. Based on the current literature, decreased cardiac acetylation, either by activation of Sirt1 or inhibition of p-300-HAT, appears to induce similar responses, such as inhibition of proinflammatory and profibrotic transcription factors, as well as activation of antioxidant enzymes, that ultimately preserve cardiac function (Table 2) [81-83].

3.3. Honokiol. Honokiol, a biphenolic compound obtained from the bark of the magnolia tree, was recently evaluated in a murine model of cardiac hypertrophy and fibrosis [37]. Remarkably, the authors demonstrated that honokiol was not only capable of preventing agonist-induced heart failure but it also reversed preexisting fibrosis and ventricular failure. The cardioprotective effects of honokiol were associated with a dose-dependent increase in Sirt3 activity. Regarding the mechanism of action, the authors showed that honokiol entered mitochondria and directly interacted with Sirt3, although the precise binding site for activation remains unclear.

3.4. Oroxylin A. Oroxylin A (OA) is derived from the root of Scutellaria baicalensis. Based on its chemical structure, with hydroxyl groups at C-5 and C-7 and a methoxy group at C-6, it is classified as a flavone [85]. As demonstrated in pharmacokinetic studies involving animal models, OA is highly bioavailable after oral infection, which increases its potential as a bioactive compound [85]. Previous studies reported that OA functioned as a Sirt3 activator in human breast cancer cells [86] and as an acute Sirt3 activator in an in vitro model of cardiac myocyte insulin resistance [87,88]. Via the activation of Sirt3, OA prevented loss of contractile function in response to insulin overstimulation, as evidenced by preserved peak shortening [88]. OA also appeared to reduce angiotensin-induced hypertrophy and cell death in cardiac myoblasts, pointing to a potential cardioprotective effect. In addition, OA decreased mitochondrial hyperacetylation and energetic debacle in a dose-dependent manner [89]. Based on the current evidence, OA appears to increase Sirt3 activity in cardiac cells, although no precise mechanism of action has been described thus far.

3.5. Other Emerging Regulators of Protein Acetylation in CVDs. Information on regulators of protein acetylation other than the aforementioned is scarce but encouraging. Details on phytochemicals capable of modulating cardiac acetylation via the activation of sirtuins in models of CVDs are presented in Figure 3. They include quercetin, epigallocatechin-3-gallate, bakuchiol, tyrosol, and berberine [81-86]. Nutraceuticals that function as activators of Sirt1 include docosahexaenoic acid, alpha-lipoic acid, sulforaphane, and caffeic acid ethanolamide, although the mechanisms by which they activate sirtuins remain to be elucidated [26,89-97]. Most of these functional molecules share common molecular targets and exert their actions, for example, by stimulation of AMPK-[alpha], eNOS, PGC1-[alpha], and superoxide dismutase or inhibition of NF-[kappa]B and proapoptotic molecules (e.g., Bax and caspase 3). Table 3 summarizes the findings of experimental models and the results obtained for each reported phytochemical, specifying the molecular pathways and targets involved.

4. Clinical Evidence for Cardioprotective Properties of Natural Modulators of Protein Acetylation

Experimental data supports cardioprotective properties of natural modulators of protein acetylation, but little is known about their effects in a clinical setting. To date, resveratrol is the only phytochemical that has been tested as a sirtuin activator in humans. As discussed previously, resveratrol mimics calorie restriction effects in vitro and in vivo. A recent study of obese patients demonstrated that supplementation with resveratrol for 30 days significantly increased Sirt1 expression via activation of AMPK and that it improved muscle mitochondrial respiration by increasing fatty acid oxidation [98]. This translated into decreased hepatic lipid accumulation and reduced inflammation [98]. The study did not measure variations in cardiac function. Nevertheless, it is well known that obesity is an independent risk factor for CVDs [1]. In this context, the observed protection against inflammation and lipid accumulation might decrease the risk of vascular and cardiac pathologies in obese patients.

In contrast to the synergetic effects of resveratrol and physical activity observed in murine models, supplementation with resveratrol blunted the cardioprotective effects achieved by 8 weeks of physical exercise in men over 60. This study detected no changes in Sirt1 expression in either group [99]. As the roles of both physical activity and resveratrol as activators of Sirt1 have been demonstrated in experimental models of senescence, it appears that the human response to both stimuli is different with regard to the activation of the AMPK/Sirt1/PGC1-[alpha] axis, as discussed previously [100].

The role of resveratrol as a Sirt1 activator was evaluated in postmenopausal woman of with a normal weight and glucose tolerance [101]. In this group, resveratrol supplementation was associated with no major improvements in metabolic parameters or modification of Sirt1 expression [101]. Although sirtuin deficiency is uncommon in healthy individuals, it has been reported in obese patients and patients with metabolic syndrome [98,102]. Additionally, sirtuin activity was decreased in a study of heart failure patients [8]. In common with vitamin supplementation in the absence of any vitamin deficit [103], supplementation with sirtuin activators is not expected to have any benefit when basal levels of Sirt1 expression and activity are normal. The aforementioned might explain why supplementation with resveratrol has a positive effect under conditions of obesity [98] but no effects under conditions of normal weight and glucose tolerance [101].

5. Bioavailability of Cardioprotective Phytochemicals

Although experimental models have revealed promising cardioprotective effects of phytochemicals, their bioactivity in the clinical setting remains to be explored. After oral ingestion of phenolic compounds, two factors mainly determine their biological activity: absorption and metabolic stability. Absorption in the small intestine varies according to the hydrophobicity of the compounds and affinity of membrane transporters, and only aglycones can be efficiently absorbed [27, 104-106]. Most polyphenols must be hydrolysed by intestinal enzymes or microflora in order to permeate the intestinal epithelium [105, 106]. Once they are absorbed and reach the liver, their stability depends on their sensitivity to metabolism by phase II enzymes.

Only a few pharmacokinetic studies of phenolic compounds have been reported in humans. A study of resveratrol absorption and metabolism in healthy subjects showed that after oral ingestion of resveratrol, around 92% of the administered dose was excreted in urine and faeces [27]. In an experimental study, the final amount of resveratrol absorbed in liver fractions was extremely low due to rapid formation of conjugates of resveratrol, mainly by sulfation and glucuronidation [104].

Some studies have explored the potential impact of functional groups on the bioavailability of polyphenols. Methylated polyphenols easily permeated the intestinal epithelium, without previous conjugation, in contrast to unmethylated compounds [104]. In the presence of hepatic phase II enzymes, methylated polyphenols were more stable than their unmethylated counterparts. These properties should encourage more in-depth studies of the potential biological effects of naturally methylated polyphenols, considering the benefits of their pharmacokinetic profiles.

Recently, the role of nanocarriers as a novel strategy to increase the bioavailability of polyphenols has been studied (reviewed in [107]). Besides increasing absorption and protecting polyphenols from enzymatic degradation, nanocarriers can be configured to release material in a controlled and prolonged manner, maintaining bioactivity for longer periods. Two studies that examined the potential of nanocurcumin as a sirtuin activator reported significant improvements in its bioactivity [82, 84]. Although neither study directly compared the biological effects of curcumin versus those of nanocurcumin, the biological effects of nanocurcumin were observed at lower concentration than that of free curcumin [42, 80, 81] (Table 2).

A number of studies have examined other nanoencapsulated polyphenols, although they did not evaluate their activity as modulators of acetylation. Recent evidence indicates that cardiac muscle and vessels are targets for nanotechnology-based therapies that could reach the myocardium through dysfunctional permeable endothelium [108]. In a murine model of heart failure, passive cardiac accumulation of high concentrations of nanocarriers occurred after a single application [108]. Compared to normal heart tissues, the accumulation of nanovectors was more than 10 times higher in the heart failure murine model [108]. This approach using nanocarriers, represents a potential avenue for functional molecules, which may be translated into innovative treatments to improve patient CVD outcomes.

Recent studies revealed that the microbiome can significantly modify the extent to which phenolic compounds are metabolized [109, 110]. It is well known that intestinal and colonic microorganisms vary according to a patient's physiological status [111]. Thus, preliminary pharmacokinetic studies should ideally be performed in systems simulating both healthy and unhealthy gastrointestinal tracts.

6. Potential Toxicity of Phytochemicals

Although numerous health benefits are associated with the consumption of phytochemicals, caution is needed when selecting an exploratory dose because of their hormetic behaviour. Plants synthesize phytochemicals and activate adaptive molecular pathways to protect themselves against cellular stress. Although exogenous administration of phytochemicals to organisms can have protective effects at specific doses, they can also have prooxidant and cytotoxic effects at relatively high concentrations [112].

Regarding cardioprotection and the toxicity of phytochemicals, a recent study compared heart function in rats after 21 days of supplementation with increasing doses of resveratrol [113]. The authors reported that 2.5 mg/kg/d and 25 mg/kg/d protected ex vivo against I/R induced injury but that higher doses had adverse effects on cardiac function [113]. Interestingly, in this study, both rats and rabbits showed greater tolerance to a synthetic resveratrol formulation, Longevinex, which contains small amounts of quercetin and ferulic acid, than to resveratrol alone. This finding might be explained by increased flavonoid stability and metabolic competition when administered in combination than when administered singly, with the combination therapy potentially decreasing, as well as having a prooxidant effect. Clinical trials reported no adverse effects of resveratrol doses ranging from 0.4mg/kg/d to 5g/d [114, 115]. The apparent higher tolerance observed in humans than in animal models might be explained by lower resveratrol bioavailability and metabolic competition with other nutrients present in a patient's diet, in addition to differences in the gastrointestinal tracts of humans and animals.

To our knowledge, there are no reports on the pharmacokinetic profiles of the remaining reviewed molecules in humans. However, as shown by in vitro and in vivo studies, most phytochemicals exhibit a similar bimodal dose-response curve. Supplementation with epigallocatechin-3-gallate at 30 and 60 mg/kg abolished anxiety in mice [116,117]. Remarkably, increasing the dose to 100 mg/kg induced 100% mortality in less than 24h [116,117]. Epigallocatechin-3-gallate is the most abundant catechin in green tea. Although moderate consumption of this beverage has been associated with health benefits, more than 1L per day increased the risk of cancer in humans [118], although this finding was attributed to the temperature of the beverage and not only to its bioactive substances [118, 119]. Although many studies in the literature support the potential cardio-protective effects of the phytochemicals reviewed in the present work, in-depth studies of their bioavailability and pharmacokinetic profiles are missing. Further research is needed to address this issue.

7. Conclusion

Protein hyperacetylation is associated with the development of several CVDs, including atherosclerosis, hypertension, cardiac hypertrophy, and heart failure. The underlying mechanisms include activation of proinflammatory cytokines and proapoptotic molecules and inhibition of mitochondrial biogenesis and function, in addition to downregulation of enzymes involved in antioxidant defence. Decreased expression and activity of the deacetylases Sirt1, Sirt3, and Sirt6 are associated with the development and progression of the aforementioned pathologies.

The potential cardioprotective roles of several phytochemicals as regulators of sirtuin-mediated protein deacetylation have been studied. Preclinical evidence suggests that by activating Sirt1 and/or Sirt3, some bioactive phytochemicals can protect the cardiovascular system from the negative consequences of hyperacetylation (Figure 4). In the clinical setting, only resveratrol has been validated as a Sirt1 activator in obese patients, with conflicting results found in other clinical trials performed with men over 60 and postmenopausal women. As healthy subjects show no benefit from supplementation, it appears that sirtuin activators should be evaluated only in specific patient groups, such as obese subjects or those with metabolic syndrome or heart failure, with a previous reported deficiency. Pharmacokinetic studies in humans are required to determine the optimum dose selection. The low bioavailability of phytochemicals limits their biological effects. Various strategies, including nanodelivery systems, aimed at overcoming this problem are currently under way. Initial results of these studies appear promising.

Conflicts of Interest

The authors declare no conflict of interest.


This work was partially supported by Xignus Research Foundation as well endowed Chair in Cardiology/Grupo de Enfoque Medicina Cardiovascular Tec de Monterrey, CONACYT Grant CB-256577, Fronteras de la Ciencias 0682 (Gerardo Garcia-Rivas), and Red Tematica Farmoquimicos del CONACYT. Niria Trevino-Saldana was supported by a graduate scholarship program from CONACYT. The authors thank Dr. Aurora Valdez for her methodological assessment during the organization of the manuscript.


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Niria Trevino-Saldana (1) and Gerardo Garcia-Rivas (1,2)

(1) Catedra de Cardiologia y Medicina Vascular, Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Monterrey, Mexico

(2) Centro de Investigacion Biomedica, Hospital Zambrano Hellion, Tec Salud del Sistema, Tecnologico de Monterrey, Monterrey, Mexico

Correspondence should be addressed to Gerardo Garcia-Rivas;

Received 6 June 2017; Revised 26 August 2017; Accepted 25 September 2017; Published 6 November 2017

Academic Editor: Vas Naryanaswami

Caption: Figure 2: Targeted pathways by sirtuins in cardiac fibroblasts, cardiac myocytes, and in the vascular system. Sirt1 and Sirt6 prevent fibrosis and fibroblast hypertrophy by repressing growth factors such as TGF-[beta] and IGF1, as well as inflammatory cytokines like TNF-[alpha] [24,25]. At the vascular level, Sirt1 activation induces vasodilatation and promotes cell survival via deacetylation of eNOS and p53. The activity of eNOS and p53 increases in a Sirt1-dependent manner [26], whereas Sirt6 inhibits VCAM and TNFS protecting against atherosclerosis [27]. Sirt1 in the cardiac myocyte promotes mitochondrial biogenesis and function mainly through the activation of PGC1-[alpha] and Sirt3 [28], which activates mitochondrial dehydrogenases, enzymes from the electron transport chain, and the synthase and represses cyclophilin D, protecting the cell from the opening of the mitochondrial permeability transition pore [29-38]. Nuclear sirtuins 1 and 6 prevent cardiac hypertrophy and inflammation through the inactivation of the NF-[kappa]B pathway [24, 25], as well as IGF-Akt by Sirtuin 6 [25]. Sirtuins 1 and 3 are also regulators of oxidative stress through the regulation of FoxOs, and both promote DNA repair through the activation of Ku70 [39-42].

Caption: Figure 3: Phytochemicals with beneficial effects in CVDs through modulation of protein acetylation.

Caption: Figure 4: Cardioprotective effects of sirtuin activators and the molecular pathways involved. Red boxes state the phytochemicals regulating the activity of Sirt1, Sirt3, or both, as indicated by the green connecting lines. Green lines indicate activation of the indicated targets, whereas red lines indicate inhibition. Gray boxes indicate inhibition of cellular responses and white boxes indicate stimulation of them. CAE: caffeic acid ethanolamide; a-LA: alpha-lipoic acid; DHA docosahexaenoic acid.
Table 1: Cardioprotective effect and mechanism of action
of resveratrol in preclinical studies.

Target HDAC              Molecular                Experimental
or HAT                    pathway                     model

[up arrow]        [up arrow] PGC-1[alpha]         TAC induced
Sirt1                 [up arrow] Bcl2         myocardial infraction
                     [down arrow] Bax,               In vivo
                         caspase 3              Hypoxia induced
                   [up arrow] SOD, SDH,            dysfunction
                       Cyt-c oxidase                In vitro

[up arrow]             [down arrow]            TAC induced heart
Sirt3                 TGF-[beta]/Smad3               failure
                                                     In vivo

[up arrow]             [up arrow] SOD            Chronic heart
Sirt1                                             failure model
                                                     In vivo
                                              Ang II or antimycin
                                                    A induced
                                                oxidative stress
                                                    In vitro

[up arrow]             [up arrow] SOD             Dox-induced
Sirt3                                             mitochondrial
                                                     In vivo
                                                    In vitro

[up arrow]          [down arrow] p38MAPK       Dox-induced heart
Sirt1              [down arrow] caspase 3            failure
                      [down arrow] Bax               In vivo
                      [up arrow] Bcl-2
                      [up arrow] SOD1

[up arrow]            [up arrow] AMPK             Dox-induced
Sirt1                                            cardiotoxicity
                                                    In vitro

[up arrow]            [down arrow] p53            Dox-induced
Sirt3                [down arrow] Bax,           cardiotoxicity
                           Cyt-c                     In vivo

[up arrow]           [down arrow] USP7            Dox-induced
Sirt1                [down arrow] p300          cardiotoxicity in
                     [down arrow] Bax,           young and aged
                         caspase 3                   hearts
                      [down arrow] p53               In vivo
                    [up arrow] PI3K-Akt
                  [down arrow] TNF-[alpha]

[up arrow]             [down arrow]                 Exercise
Sirt1                FAS/FADD/caspase 8           during aging
                   [down arrow] caspase 3            In vivo
                      [up arrow] FoxO3

[up arrow]         [down arrow] ac-FoxO1              Aging
Sirt1              [down arrow] Bim, Bax             In vivo
                      [down arrow] p53

[up arrow]             [up arrow] SOD         High glucose-induced
Sirt1                  [up arrow] GSH            mitochondrial
                                                oxidative stress.
                                                    In vitro

[up arrow]            [down arrow] p53         Hypertension model
Sirt1                 [up arrow] SDF-1               In vivo

In T1DM:             [down arrow] B-MHC           T1DM-induced
[up arrow]            [down arrow] Akt           cardiomyopathy
Sirt1,                                               In vivo
Sirt2, Sirt3,                                     T2DM-induced
and Sirt5.                                       cardiomyopathy
In T2DM:                                             In vivo
[up arrow]
Sirt1 and Sirt2
[down arrow]
Sirt3, which
was initially

[up arrow]             [down arrow]            [H.sub.2][O.sub.2]-
Sirt1,                   caspase 3              induced apoptosis
Sirt3,                                              In vitro
Sirt4, and

Most effects         [up arrow] SOD1,                In vivo
abolished               SOD3, GPx1,             Apo-lipoprotein
when using               catalase.               E Knockout mice
sirtinol               [down arrow]
                         NOX2, NOX4
                      [up arrow] GTP
                      cyclohidrolase 1
                       and biopterin

Target HDAC               Cardiovascular
or HAT                         effect                 Reference

[up arrow]                [up arrow] LVEF               [52]
Sirt1                  [down arrow] fibrosis
                       [down arrow] apoptosis

[up arrow]             [down arrow] fibrosis            [53]
Sirt3             [down arrow] collagen deposition
                  [down arrow] cardiac hypertrophy
                  Prevented decrease in cardiac FS
                    Preserved diastolic function

[up arrow]                 [up arrow] FS                [54]
Sirt1                     [up arrow] LVEF
                        [up arrow] survival
                       [down arrow] apoptosis

[up arrow]            [down arrow] oxidative            [32]
Sirt3                          stress
                          [up arrow] ATP
                      mitochondrial production

[up arrow]                 [up arrow] FS                [55]
Sirt1                  [down arrow] apoptosis
                   [down arrow] oxidative stress

[up arrow]              [up arrow] survival             [56]

[up arrow]             [down arrow] apoptosis           [57]
Sirt3              Attenuated loss of diastolic
                       and systolic function.

[up arrow]                 [up arrow] FS                [58]
Sirt1                      [up arrow] EF
                         [down arrow] LVEDS
                       [down arrow] apoptosis

[up arrow]                 [up arrow] FS                [41]
Sirt1                  [down arrow] fibrosis
                       [down arrow] apoptosis

[up arrow]                 [up arrow] FS                [40]
Sirt1                     [up arrow] LVEF
                       [down arrow] fibrosis
                       [down arrow] apoptosis

[up arrow]            [down arrow] oxidative            [59]
Sirt1                          stress

[up arrow]            [down arrow] hypertrophy          [60]
Sirt1                [up arrow] bioavailable NO
                       [down arrow] apoptosis

In T1DM:                   In T1DM rats:                [61]
[up arrow]          [down arrow] cardiac atrophy
Sirt1,                     In T2DM rats:
Sirt2, Sirt3,          [down arrow] cardiac
and Sirt5.                  hypertrophy
In T2DM:
[up arrow]
Sirt1 and Sirt2
[down arrow]
Sirt3, which
was initially

[up arrow]             [down arrow] apoptosis           [62]
Sirt4, and

Most effects           [down arrow]Oxidative            [63]
abolished                      stress
when using            Reversed eNOS uncoupling

AMPK: adenosine monophosphate-activated kinase; Ang II: angiotensin
II; B-MHC: myosin heavy chain B; Cyt-c: cytochrome c; Dox: doxorubicin;
FS: fractional shortening; Gpx1: glutathione peroxidase 1; GSH:
glutathione; LVEF: left ventricular ejection fraction; NE:
norepinephrine; NOX: NAD(P)H oxidase; PGC1-[alpha]: peroxisome
proliferator activator of transcription (PPARy) co-activator
1[alpha]; TAC: transverse aortic constriction; T1DM: type 1
diabetes mellitus; T2DM: type 2 diabetes mellitus; SDF-1: stroma
cell derived factor 1; SHD: succinate dehydrogenase; SOD: superoxide
dismutase. USP7: ubiquitin-specific-processing protease 7.

Table 2: Cardioprotective effect and mechanism of action
of curcumin in preclinical studies.

Target HDAC         Molecular
or HAT                pathway            Experimental model

[up arrow]         [down arrow]             TAC induced
Sirt1              TGF-[beta],          myocardial infraction
                     Col III,                  In vivo
                       Col I               Ang II-Induced
                                              In vitro

[up arrow]        [up arrow] SOD         Isolated ischemia-
Sirt1            [up arrow] Bcl2,         reperfusion model
                 [down arrow] Bax              Ex vivo
                                       TAC induced myocardial
                                               In vivo
                                         Simulated ischemia-
                                          reperfusion model
                                              In vitro

[up arrow]          [up arrow]           [H.sub.2][O.sub.2]-
Sirt1                  eNOS              induced endothelial
                   [down arrow]         premature senescence
                        p21                   In vitro

[up arrow]          [up arrow]            Atherogenic model
Sirt1               AMPK[alpha]               In vitro
                    [up arrow]
                  [up arrow] ATP
                 binding cassette
                   transporter 1

[down arrow]       [down arrow]             LPS-induced
p300-HAT          acetylation of         cardiac hypertrophy
                 histones 3 and 4              In vivo

[down arrow]       [down arrow]         High glucose-induced
p300-HAT         TGF-[beta]/Smad2        cardiac hypertrophy
                                              In vitro
                                         cardiac dysfunction
                                               In vivo

[down arrow]    [down arrow] GATA4     TAC induced myocardial
p300-HAT           [down arrow]              Infraction
                    NF-[kappa]B                In vivo
                   [down arrow]        PE-induced hypertrophy
                  acetylation of              In vitro
                 histones 3 and 4

[down arrow]       [down arrow]        TAC induced myocardial
p300-HAT              Ac-p53                 Infraction
                [down arrow] ANF,              In vivo
                    [beta]-MHC             Ang II-Induced
                [down arrow] Bax,            hypertrophy
                 Cyt c, caspase 3,            In vitro
                     and PARP

[down arrow]    [down arrow] GATA4        Hypoxia-induced
p300-HAT         [down arrow] p53            hypertrophy
                                              In vitro

Target HDAC
or HAT               Cardiovascular effect        Reference

[up arrow]         [down arrow] infract area         [77]
Sirt1                [down arrow] fibrosis
                    [down arrow] hypertrophy

[up arrow]          Improved post-ischemic           [42]
Sirt1                   cardiac function
                    [down arrow] myocardial
                          infract size
                  [down arrow] apoptotic index
                 [down arrow] oxidative stress
                  Preserved serum CK activity
                 [down arrow] LDH serum levels

[up arrow]          [down arrow] premature           [79]
Sirt1                      senescence
                 [down arrow] oxidative stress
                     [down arrow] apoptosis
                     Preverved NO synthesis

[up arrow]              Antiatherogenic              [78]
Sirt1                [down arrow] cellular
                    [up arrow] cholesterol
                       efflux from THP-1

[down arrow]         [down arrow] cardiac            [83]
p300-HAT                  hypertrophy

[down arrow]         [down arrow] cardiac            [81]
p300-HAT                  hypertrophy
                  [down arrow] extracellular
                       matrix production
                     [up arrow] diastolic

[down arrow]     [down arrow] LV wall thickness      [77]
p300-HAT          Preserved systolic function
                    [down arrow] hypertrophy

[down arrow]        [down arrow] hypertrophy         [80]
p300-HAT             [down arrow] apoptosis

[down arrow]       Stabilized mitochondrial          [82]
p300-HAT               membrane potential
                 Restored lactate, acetyl-coA
                  pyruvate, and glucose levels

AMPK: adenosine monophosphate-activated kinase; ANF: atrial natriuretic
factor; Ang II: angiotensin II; B-MHC: myosin heavy chain B; CK:
creatine kinase; Cyt-c: cytochrome c; EF: ejection fraction; eNOS:
endothelial nitrix oxide synthase; LDH: lactate dehydrogenase;
LXR-[alpha]: liver X receptor [alpha]; LV: left ventricular; NE:
norepinephrine; PAI-I: plasminogen activator inhibitor 1; PARP:
poly(ADP-ribose) polymerase; PGC1-[alpha]: peroxisome proliferator
activator of transcription (PPARy) coactivator 1[alpha]; PE:
phenylephrine TAC: transverse aortic constriction; SOD: superoxide

Table 3: Other emerging cardioprotective phytochemicals
regulating protein acetylation.

                      Target HDAC           Molecular
Phytochemical            or HAT               pathway

Honokiol            [up arrow] Sirt3       [down arrow]
                                         collagen, B-MHC,
                                              and ANF

Oroxylin A          [up arrow] Sirt3        [up arrow]

Epigallocatechin-   [up arrow] Sirt1        [up arrow]
3-gallate                                  AMPK-[alpha]
                                          [up arrow] eNOS

Quercetin           [up arrow] Sirt1       [down arrow]
                                         [down arrow] Nrf2
                                            [up arrow]
                                          [up arrow] eNOS
                                         [down arrow] NOX2
                                         [down arrow] NOX4
                                           [down arrow]

Berberine           [up arrow] Sirt1      [up arrow] SOD
                                         [up arrow] Bcl-2
                                        [down arrow] Bax,
                                             caspase 3

Bakuchiol           [up arrow] Sirt1        GC-1[alpha]
                                          [up arrow] Bcl2
                                        [down arrow] Bax,
                                             caspase 3
                                         [up arrow] SOD,
                                            SDH, Cyt-c

n-Tyrosol           [up arrow] Sirt1      [up arrow] Akt
                                          [up arrow] eNOS
                                         [up arrow] Foxo3a

[alpha]-            [up arrow] Sirt1       [down arrow]
Lipoic acid                                   PARP-2

Docosahexaenoic     [up arrow] Sirt1      [up arrow] eNOS

Sulforaphane        [up arrow] Sirt1     [up arrow] Nrf2,
                                            NQo1, HO-1
                                       [down arrow] PAI-I,
                                         CTFG, TGF-[beta]
                                          Preserved LKB1/

Caffeic acid        [up arrow] Sirt1     [up arrow] SOD,
ethanolamide        [up arrow] Sirt3       HIF1-[alpha]

Phytochemical                Model

Honokiol              TAC induced heart
                         failure model
                            In vivo
                        PE and Ang II-
                        induced cardiac
                           In vitro

Oroxylin A             Insulin-induced
                      cardiac dysfunction
                           In vitro

Epigallocatechin-       High-fat diet-
3-gallate                   induced
                            In vivo

Quercetin                High-glucose-
                           In vitro

                       oxidative stress
                           In vitro

Berberine            Ischemia/reperfusion-
                     myocardial Infraction
                            In vivo
                      Simulated ischemia/
                           In vitro

Bakuchiol            Ischemia reperfusion-
                     myocardial infraction
                            Ex vivo
                      Simulated ischemia/
                       reperfusion model
                           In vitro
                     Rat cardiac myocytes

n-Tyrosol                TAC induced
                            In vivo

[alpha]-                 TAC-induced
Lipoic acid           cardiac hypertrophy
                            In vivo
                        Ang II-induced
                           In vitro

Docosahexaenoic            In vitro
acid                        Ex vivo

Sulforaphane             T2DM-induced
                            In vivo

Caffeic acid            Isoproterenol-
ethanolamide            induced cardiac
                            In vivo
                           In vitro

Phytochemical                  effect             Reference

Honokiol                   Blocks cardiac            [37]
                       hypertrophic response
                      Ameliorates preexisting
                      [down arrow] oxidative

Oroxylin A               Preserved cardiac           [87]

Epigallocatechin-       [down arrow] serum           [90]
3-gallate                   cholesterol
                      [down arrow] oxidative
                        Improved morphology
                        of myocardial tissue

Quercetin                 [down arrow] ROS           [89]
                       [down arrow] autophagy

                      Preserved mitochondrial        [91]
                           [down arrow]

Berberine              [down arrow] infract          [92]
                      [down arrow] oxidative
                       [down arrow] apoptosis
                          [down arrow] LDH
                        Maintained LVEF and
                     Inhibited increase in IL-6
                          and TNF-[alpha]

Bakuchiol              [down arrow] apoptosis        [93]
                      [down arrow] oxidative

n-Tyrosol            [down arrow] infract size       [94]
                       [down arrow] apoptosis
                       [down arrow] fibrosis
                          [up arrow] LVIDd
                           [up arrow] EF
                           [up arrow] FS

[alpha]-               [down arrow] cardiac          [95]
Lipoic acid                 hypertrophy

Docosahexaenoic       [up arrow] NO synthesis        [26]
acid                  [up arrow] bioavailable

Sulforaphane           [down arrow] cardiac          [96]
                       [down arrow] cardiac
                       [down arrow] cardiac
                         lipid accumulation
                      [down arrow] oxidative
                     [down arrow] inflammation
                       [down arrow] fibrosis

Caffeic acid              Restored oxygen            [97]
ethanolamide             consumption rates
                        Preserved ATP levels
                       [down arrow] cardiac
                      [down arrow] oxidative
                      Preserved mitochondrial

AMPK: adenosine monophosphate-activated kinase; ANF: atrial natriuretic
factor; Ang II: angiotensin II; B-MHC: myosin heavy chain B; CTFG:
connective tissue growth factor; Cyt-c: cytochrome c; Dox: doxorubicin;
EF: ejection fraction; eNOS: endothelial nitrix oxide synthase; FS:
fractional shortening; HIF1-[alpha]: hypoxia inducible factor
1-[alpha]; HO-1: heme oxygenase; LDH: lactate dehydrogenase; LKB1;
liver kinase B 1; LVID internal diameter in diastole; left ventricular,
LVEF: left ventricular ejection fraction; NE: norepinephrine; NQo1:
NAD(P)H quinone dehydrogenase 1; PAI-I: plasminogen activator
inhibitor 1; PARP-2: poly(ADP-ribose) polymerase 2; PGC1-[alpha]:
peroxisome proliferator activator of transcription (PPARy)
coactivator 1[alpha]; PE: phenylephrine TAC: transverse aortic
constriction; T2DM: type 2 diabetes mellitus; SHD: succinate
dehydrogenase; SOD: superoxide dismutase.

Figure 1: (a) [NAD.sup.+]-dependent deacetylation reaction
performed by sirtuins. [N[D.sup.+] is synthesized from its
precursor NMN and degraded into NAM+ acetyl-ADP-ribose once
sirtuins utilize it for their activation [10-12]. Activated
sirtuins interact with their target protein and transfer the
acetyl group from target lysine residues to ADP-ribose.
(b) Sirtuins1-7, their subcellular localization, and the
enzymatic activity they perform; yellow stars indicate
deacetylase activity [13, 14, 17, 18]. NAD: nicotinamide
dinucleotide; NMN: nicotinamide mononucleotide; Nmnat:
nicotinamide mononucleotide adenylyltransferase; Nampt:
nicotinamide phosphoribosyltransferase.

             Cellular            enzymatic
Sirtuin     compartment            action

Sirti        Nucleus            Deacetylase *
Sirt2       Cytoplasm           Deacetylase *
          during mitosis
Sirt3      Mitochondria         Deacetylase *
Sirt4      Mitochondria    ADP-ribosyltransferase
Sirt5      Mitochondria        Desuccinylase
Sirt6         Nucleus      ADP-ribosyltransferase
                                Deacetylase *
Sirt7        Nucleolus          Deacetylase *
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Article Details
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Author:Trevino-Saldana, Niria; Garcia-Rivas, Gerardo
Publication:Oxidative Medicine and Cellular Longevity
Article Type:Report
Date:Jan 1, 2017
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