Statins and Epigenetics: A Putative Mechanism for Explaining Pleiotropic Effects

Abstract

Statins remain the most efficient hypolipidemic agent and their use is pivotal in primary, secondary, and tertiary treatment of cardiovascular disease, reducing both morbidity and mortality. Statins target 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes conversion of HMG-CoA to mevalonate, the “committed and rate limiting step” in hepatic production of cholesterol. Genetic predilections for hypercholesterolemia are known to be responsible for substantial morbidity and mortality from cardiovascular disease. Environmental or lifestyle factors such as dietary fat and carbohydrate may also contribute to cardiovascular disease mortality by both genetic and epigenetic mechanisms. Besides lipid-lowering, statins have pleiotropic effects which may contribute to their protection against cardiovascular and several other diseases wherein hypercholesterolemia is a risk factor. Evidence is emerging that the clinical outcomes of many diseases are improved when modifications of environmental or lifestyle factors play integral roles in treatment and preventive prescriptions. This chapter is, therefore, intended to inform physicians and other health care professionals about the environment-gene interactions underlying the main and pleiotropic effects of statins which may be employed to improve the efficacy of statin therapies.

1. Introduction

The American Heart Association reported in 2018 that about 92.1 million American adults (i.e., more than one in four persons) had a cardiovascular disease [1]. This prevalence rises progressively with age, from 6 percent at age 20 to 77 percent at age above 75 years. Cardiovascular diseases have claimed more lives than all forms of other diseases and is responsible for 40 percent of all deaths, almost 1 million each year. Among all the cardiovascular diseases, coronary heart disease (CHD) remains the leading cause of death by 43.8 percent, followed by stroke which accounts for 16.8 percent, high blood pressure 9.4 percent, heart failure 9 percent, arterial diseases 3.1 percent and other cardiovascular disease account for 17.9 percent [1]. The annual total costs of cardiovascular diseases are estimated to be more than $329.7 billion, both direct costs and indirect costs in lost productivity. Hence, there is a need to explore novel ways to decimate this disease burden.

An elevation in the concentration of some unhealthy blood lipids have shown to contribute largely to the pathogenesis of several cardiovascular diseases [2]. Hence combination of appropriate lifestyle changes and drug therapy can result in a decline of mortality rate caused by several cardiovascular events by 30–40% [3, 4]. One of the commonly used drugs is statin. It comprises a class of medications prescribed to treat patients with elevated low-density lipoprotein (LDL) by lowering cholesterol synthesis and promoting LDL catabolism [5]. Statins work by inhibiting the synthesis of cholesterol in the liver through inhibition of HMG-CoA reductase enzyme, which is known for driving the first committed and rate limiting enzymatic step in cholesterol synthesis [4]. Competitive inhibition of this enzyme reduces cholesterol synthesis and, ultimately, the circulating plasma concentrations of cholesterol. HMG-CoA reductase activity is controlled by several mechanisms: (1) rate of synthesis of HMG-CoA; (2) translation of HMG-CoA; (3) degradation of HMG-CoA; and (4) phosphorylation of HMG-CoA. This reduction in plasma cholesterol accounts for the therapeutic benefit of statins in reducing atherogenesis, plaque stabilization, and inhibiting thrombus formation [5, 6]. Studies in patients’ taking statin have revealed 34–37% reduction in major cardiovascular events and 14–29% reduction in overall mortality. The statin drugs include lovastatin, simvastatin, pravastatin, cerivastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin, etc.

Statins can elicit secondary, pleiotropic effects beyond lowering the blood cholesterol level. Some of the pleiotropic effects of statins appear to be linked to epigenetic mechanisms [7, 8]. Medical epigenetics is the science of unraveling the link between environmental factors and changes in expression of the genes which make individuals more, or less, susceptible to diseases. During cellular differentiation and function, there are molecular signals that turn genes on and off as needed by reversibly modifying transcription of the DNA into messenger RNA (mRNA) and translation of the DNA by transfer RNA (tRNA) into proteins without impacting the sequence of the DNA such as occurs with mutagenesis. The two most studied mechanisms are methylation of the DNA and acetylation of the histone proteins which provide tightly coiled DNA (heterochromatin) with a structural framework making up chromosomes. MicroRNAs (miRNA) play roles in epigenetics by suppressing translation. DNA methylation involves transfer of methyl groups from S-adenosyl methionine to the DNA nucleotides, generally, for silencing transcription and therefore inhibiting or downregulating expression of a particular gene. Histone acetylation uncoils the heterochromatin form of DNA making it available for transcription as euchromatin. Histone acetylation works by activating or inhibiting histone acetyltransferases (HATs) and histone deacetylases (HDACs), thereby increasing, or decreasing, gene expression. Exposure to environmental stressors like toxins, pollutants, temperature, and even some dietary components also initiate epigenetic modifications which may even be passed onto the next generation of offspring when exposures occur in utero. Other epigenetic changes could be due to numerous disorders, aging, and drugs such as statins [9].

2. Epigenetic mechanisms of statins

Statins are implicated in modifying gene expression by the epigenetic mechanisms of histone acetylation, DNA demethylation and upregulation or downregulation of miRNA [10, 11]. Studies have shown that application of a statin to cell cultures increases acetylation of histones 3 and 4 (H3, H4) [12, 13, 14] and decreases the production of mRNA for HDACs [10]. Four different studies have demonstrated inhibition of the active sites of HDACs [10, 12, 14, 15]. This epigenetic modification mechanism by statin is purported to mimic the actions of some HDAC inhibiting anticancer drugs such as belinostat, chidamide and romidepsin [16]. Statins are also implicated in demethylation of DNA by stimulating DNMTs found in the promoter regions of tumor suppressor genes [10, 11]. One statin in particular, simvastatin, is shown to downregulate gene expression via the mechanisms of inhibiting histone methyltransferases (HMTs), and therefore demethylation, of histone H3 at lysine, abbreviated “K” which is the 27th amino acid of histone H3 (H3K27) [17]. This epigenetic modification by statins appears to mimic the actions of the DNMT inhibiting anticancer drugs decitabine and azacytidine [16].

2.1 Epigenetic mediated pleiotropic effects of statins on cancer cell lines

Most cancerous cells possess HDAC activity that tends to promote cellular proliferation [18]. In. that regard, lovastatin is shown to inhibit HDAC1, HDAC2 and HDAC3 with increased acetylation of histone H3 which, in turn, appears to increase expression of cyclin-dependent kinase inhibitor 1 (p21), an intracellular mediator of apoptosis [14]. Statins in combination with an HDAC inhibitor seem to increase apoptosis of cancer cells and to also decrease the toxic adverse inflammatory effects compared to administering the HDAC inhibitor as a single drug [19, 20]. Simvastatin is reported to alter expression of more than 400 miRNAs, further showing its anticancer potential [10]. Th anticancer effects of statins appear to be mediated by targeting mRNAs involved in cell-cycle arrest, cellular proliferation, and angiogenesis. Examples of the role of statins are MiR-182 which has been shown to be a potent down-regulator of the anti-apoptotic protein Bcl-2, thereby facilitating apoptosis. Upregulation of miR-612 exhibits anticancer activity by making cancer cells more responsive to chemotherapeutic agents, and miR33b has been shown to downregulate c-Myc, a proto-oncogene that regulates transcription [10, 21, 22].

2.2 Anti-inflammatory and anti-atherosclerotic pleiotropic effects of statins

Statins appear to have properties which increases their efficacy in preventing adverse cardiovascular events [5, 23]. These pleiotropic anti-inflammatory and anti-atherosclerotic effects of statins involve the following mechanisms: optimizing endothelial functions [5], reducing metalloproteinase production in the extracellular matrix of endothelial cells which, in turn, increases the production of the main mediators of vasodilation such as nitric oxide [24, 25], inhibition of platelet aggregation, promoting atherosclerotic plaque stabilization by decreasing vascular inflammation [26, 27], enhancing myocardial parasympathetic responsiveness [28], moderating autonomic myocardial stimulation thus increasing myocardial perfusion [28, 29], angiogenesis upregulation, reducing inappropriate cardiac remodeling, upregulating baroreceptor sensitivity [30], downregulating cerebral vasospasm [31, 32], and reduction in expression of the angiotensin II type I receptor mediating vasoconstriction [33].

2.3 Molecular and epigenetic basis for the anti-inflammatory and anti-atherosclerotic properties of statins

Statins are implicated in activation of epigenetic mechanisms that increase the acetylation of histones 3 and 4 which, in turn, decrease the activity of macrophages [12]. Macrophages are the main immune cells found in atherosclerotic plaques and are, therefore, the main determinants of the inflammatory and atherosclerotic potential of such plaques. During cholesterol synthesis, there are lots of isoprenoid intermediates produced [25] such as the isoprenes geranylgeranyl and farnesyl. These intermediates are important for post-translational modification of proteins in order to covalently bind some proteins and traffic them to membranes where they function. Protein isoprenylation occur mainly on proteins containing C-terminal cysteine aliphatic amino acid (CaaX motif), and some members of the Ras and Rho GTPase family are involved in isoprenylation [23, 25]. The significance of this is that GTPases are involved in regulating cytoskeletal and intracellular signaling traffic pathway by alternating between active and inactive GTP-bound states. As a result of this alternation, they regulate cellular growth, migration, morphogenesis, and cytokine trafficking. The Rho GTPase family consist of RhoA, Rac, and Cdc42, they are known for regulating cell cycle progression, proliferation, vesicle trafficking, cell shape, and maintaining optimal microtubule functions. Some Rho associated protein kinases are involved in hypertension by modulating calcium-insensitive vascular smooth muscle contraction and coronary spasm [25]. Statins have been reported to inhibit proliferation of smooth muscle cells in the arterial wall by inhibiting RhoA isoprenylation in these cells, thus distorting membrane trafficking and gene transcription. This leads to alteration in the actin cytoskeleton and inhibition of assemblies of proteins for focal adhesion, thus enhancing endothelia cell functions [34]. An epigenetic study speculates that the potential for inhibiting Rho signaling is linked to statin induced upregulation of miRNAs [35].

Rac is another GTPase involved in atherosclerosis, known to promote inflammation by generating reactive oxygen species, by activating NADPH oxidase activity, and by binding cytoskeletal remodeling proteins like p21-activated kinase and calmodulin-binding GTPase activating proteins. Statins are shown to inhibit Rac mediated NADPH oxidase activity, thereby reducing the free radical production resulting from angiotensin II and protecting against endothelial dysfunction, as well as cardiac and smooth muscle hypertrophy [36, 37]. Statins are also shown to increase histone acetylation and expression of angiotensin-converting enzyme 2 (ACE2), thereby counterbalancing the effects of angiotensin II and indirectly ameliorating risk factors for the development of atherosclerosis [37].

The hypolipidemic effects of statins are likely responsible for the main mechanism of protection against endothelial dysfunction by reducing plasma lipid particles, which, in turn, upregulates endothelial nitric oxide synthase (eNOS) and production of nitric oxide [38]. This appears to be achieved by prolonging the half-life of eNOS with involvement of PI3K/Akt activation, RhoA geranylgeranylation, and inactivating an integral membrane protein responsible for binding eNOS in caveolae [39]. The activation of eNOS leads to reduction in ROS and deactivation of pro-inflammatory transcription factors. Statins are also shown to cross-react with sphingosine-1-phosphate (S1P) a naturally occurring bioactive lysophospholipid in G-protein-coupled S1P receptors, thereby regulating cell-to-cell and cell-to-matrix adhesion, cell migration, differentiation, and survival of endothelial cells [40]. Such effects of statins on SIP receptor mechanisms are likely to enhance endothelial responsiveness to HDL, thereby inhibiting lipid oxidation for invasion and deposition, promoting lipid transport to the liver for degradation and clearance from the circulation and, ultimately, improving endothelial function. However, the involvement of statin induced upregulation of histone acetylation and miRNAs in these lipidemia-related effects remains unknown.

High sensitivity C-reactive proteins (hsCRP) synthesized in the liver as acute phase reactants are elevated in patients with increased risk for stroke and heart attack [4]. CRP is produced in response to pro-inflammatory cytokine released during atherogenesis, thus binding to modified LDL particles within the plaques and eventually activating complement protein that enhance inflammation. Lovastatin decreases plasma levels of C-reactive protein thus reducing risk for acute coronary events in patients with relatively low plasma LDL cholesterol levels [4]. DNA methylation of CRP is an epigenetic mechanism shown to be correlated with cognitive decline (41). Because of the strong connection between cognitive decline and atherosclerosis. Whether DNA methylation patterns are correlated with atherogenesis independently of cognitive decline, should be investigated.

Studies have also shown that statins influence the regulation of endothelial progenitor cells (EPC) which play a vital role of repairing and angiogenesis at the site of vascular damage or ischemia especially in patients with coronary and peripheral vascular diseases. This process is thought to be mediated by multiple miRNAs, thus promoting the release of cytokines and endothelial cells differentiation. A clinical trial involving patients with cerebrovascular disease taking atorvastatin for eight months reported downregulation of miR34a and increased EPC blood counts [41]. A similar finding was reported in another study demonstrating downregulation of miR-221 and miR-22 expression and increased EPC peripheral blood counts after 12 months of atorvastatin treatment [42].

Other anti-inflammatory properties of statins include decreased expression of TNF-alpha and IL-1β from macrophages eventually downregulation of mononuclear leukocyte proliferation in the blood [43]. There is also inhibition of β2-integrin antigen-1, thereby decreasing lymphocyte adhesion molecules and the secretion of anti-inflammatory Th2-type cytokines [44]. A randomized control study performed by giving 40 mg of simvastatin daily to patients (n = 25) or placebo (n = 20) for two months demonstrated reductions in serum inflammatory markers, such as IL-6, IL-13, IFN-𝛾, IP-10, MCP-1, and VEGF [45]. There also is evidence from animal studies that rosuvastatin may increase the expression of CC-chemokine receptor 7 (CCR7), a key regulator of macrophage emigration. Crosstalk between DNA methylation and numerous pro-inflammatory and anti-inflammatory cytokines has been reported (46). These findings appear support the main hypothesis of the present review that epigenetic mechanisms are likely to play a critical role in atherogenesis.

3. Environment: gene interaction for statins in cardiovascular regulation: emphasis on autonomic balance and baroreceptor sensitivity

Statins have the potential of sympathetic activity modulation in the heart and great vessels, coupled with an increase in baroreceptor sensitivity. Some underlying mechanism involve increase in endothelial nitric oxide synthase (eNOS) thus improving endothelial function and baroreflex control of blood pressure from the central nervous system. Moreira et al. corroborated statin’s ability to enhance aortic depressor nerve activity and better arterial distensibility by increasing the number of carotid elastic lamella with resultant reduction in vessel intima thickness. Reducing the mechanical stress on the walls of the carotid and aortic arteries plays vital role at baroreceptor sensitivity enhancement [46]. Angiotensin 1 receptor (AT-1) and nicotinamide adenine dinucleotide phosphate oxidase are also modulated by statins thus potentiating the ability of reducing peripheral sympathetic activity [47]. There is evidence that oral atorvastatin treatment in hypertensive rat model improves sympathovagal balance by reducing reactive oxygen species in the rostral ventro-lateral medulla and increasing eNOS expression in the nucleus tractus solitarius [48].

Tetraspanin 2 protein (TSPAN2) vastly expressed in vascular tissue has been implicated in maintaining vascular smooth muscle contractile ability and its cellular differentiation. This protein is linked to large artery atherosclerosis-related stroke due to its proinflammatory, highly proliferative and migratory tendencies. An epigenome-wide association study identified that 0.1% decrease in DNA methylation at cg23999170 results in increased TSPAN2 expression thus leading to a 5 mmHg increase in diastolic blood pressure [49]. TSPAN2 signaling is regulated by TGFB1/Smad. TGFB1/Smad signaling is a target of statins for preventing atherogenesis. These findings implicate statins as a potential mediator of changes in DNA methylation associated with the expression of TSPAN2. Future studies should determine whether statins induce changes in DNA methylation which may protect arteries from atherogenesis by increasing the expression of TSPAN2 and from hypertension by increasing baroreceptor sensitivity. These findings seem to support the concept of crosstalk between epigenetic regulations of vascular structure and baroreceptor sensitivity for protection against both atherogenesis and hypertension.

4. Environment: gene interaction for statin-induced type 2 diabetes

Long term statin use especially at higher doses has been shown to increase the risk of users developing type-2 diabetes [50]. This stems from impaired secretion of insulin from the beta-cells of the pancreas, decreased insulin sensitivity, and poor utilization of insulin at the peripheral tissues. Some of the epigenetic modification linked to statin therapy includes statin potential to methylate DNA and alter miRNA expression which are known to play key role in the regulation of glucose and lipid metabolism. miRNA silences gene expression, thus affecting insulin expression, insulin sensitivity, and skeletal muscle adaptation to elevated glucose. Several studies have revealed that statin treatment can upregulate miRNA-33 family (33a and 33b) expression, which plays significant role in statin’s pleiotropic effects [22, 51].

MiRNA-33a encodes the introns of SREBP1 gene thus targeting the export of cholesterol, fatty acid metabolism, high density lipoprotein (HDL) regulation, inhibiting ABCA1 and ABCG expression. ABCA1 plays a vital role at regulating beta-cell activity in the pancreas. Inhibiting expression of such gene may cause beta-cell dysfunction due to alteration in islet cholesterol homeostasis and impaired insulin secretion [52]. miRNA-27 family have also been implicated in downregulation of low-density lipoprotein receptor-RNA (LDLR-RNA), LRP6, LDLRAP1, and indirectly upregulating PCSK9 [53]. Alteration of these proteins negatively impacts the correct binding of clathrin endocytosis of LDLR-LDL-C complex thus resulting in LDLR inefficiency and subsequently insulin resistance.

Increase in hepatic glucose production has been seen as one of the direct pleiotropic effects of statin mediated upregulation of miRNA-183/96/182 cluster [54]. Thus, resulting in higher expression of key gluconeogenic enzymes like phosphoenol pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) which may contribute to developing type-2 diabetes due to poor glycemic control. Essentially, when insulin binds to its receptor (insulin receptor- INSR), it triggers cascade of events by modulating PI3K/PDK1/Akt pathway. This signaling therefore result in metabolic effect that helps normalize blood glucose level. Upregulating some of these miRNAs negatively impact the expression of insulin receptor substrates-2 (IRS2) which may potentially affect insulin signaling and end up contributing to risk factors for insulin resistance. Also, simvastatin’s downregulation of miRNA-146a inversely alter the expression of protein tyrosine phosphatase non-receptor type 1 (PTPN1) which is known to negatively affect regulation of insulin signaling [55].

Other mechanisms through which statin predisposes one to type-2 diabetes includes limiting glucose uptake in peripheral cells. It downregulates glucose transporter-4 (GLUT-4) expression at the plasma membrane thus impairing insulin signaling. There is also statin-induced isoprenylation inhibition, Rab-4 and RhoA isoprenoid-dependent proteins which are known to aid insulin-induced translocation of GLUT-4 are impaired thus inefficient insulin signaling. It can also induce changes in hormones like leptin and adiponectin, and free fatty acid circulation. Insulin secretion from the pancreatic beta cell is mostly initiated by glucose induced ca2+ entry which is controlled by voltage gated L-type calcium channel. Simvastatin in rat model has shown to impair this channel activity thus resulting in an impairment of insulin secretion. GLUT-2 mRNA and protein expression is also inhibited by statin at the beta cells of the pancreas thus limiting the glucose uptake and metabolism.

The metabolic syndrome in men study (METSM) found 24% insulin sensitivity reduction, 12% reduction in pancreatic beta cell reduction, and 46% increase in the risk of developing type-2 diabetes mellitus (T2DM) and worsening hyperglycemia when compared to men no on statin treatment [56]. This side effect of statin portends higher risk in patients with pre-existing risk factors like higher body mass index (BMI) or HbA1c, or impaired fasting blood glucose). It is interesting to note that atorvastatin and simvastatin elicit these effects in a dose dependent fashion.

5. Final discussion

The duration of statin use that is likely to result in primary or secondary prevention of cardiometabolic events is not clearly known. But it has been observed that the lipid lowering property of statins may require 6–24 months of treatment while the endothelial-dependent vasomotor effects of statins appear to be more rapid, about 6 months from the initiation of treatment [57]. It is noteworthy that when vasodilators are given, the potential inhibition of pro-thrombotic mediators may increase stabilization of the atherosclerotic plaque and, thereby, prevent thrombotic complications. Whether these benefits are epigenetically mediated remain open to debate. Statins appear to have pleiotropic anticancer properties in vitro, as reflected in lower rates of cancers in patients using statins [58]. On the other hand, meta-analyses of clinical trials report no such anticancer effect [59]. These contradictory reports could, partly, be attributed to different statins having different biochemical properties. For example, treatment with a hydrophilic statin, pravastatin, was associated with less DNA methylation of cancer cells compared to a more lipophilic statin, simvastatin [11]. Simvastatin is reported to downregulate the expression of histone-lysine-N-methyltransferase known as EZH2, whereas pravastatin had no effect on EZH2 [17]. On the other hand, simvastatin is reported to downregulate the expression and activity of DNMTs and HDACs [15], whereas lovastatin only reduced the activity of both these enzymes without altering their expression [15]. It is noteworthy that these epigenetic mechanisms may not be connected to the therapeutic effects of statins based on evidence which supports the notion that statins can produce effects by mechanisms involving changes in phenotype and/or cell metabolism, as reported for prolonged use of metformin [60]. Similar observations have been made in the outcome of lupus patients in whom the CRP levels were correlated with the use of a particular statin; plasma CRP in lupus patients using lipophilic atorvastatin was found to be significantly lower than the CRFP levels associated with use of rosuvastatin or pravastatin [61]. Table 1 recapitulates statins’ potential epigenetic mechanisms and effects.

Potential pleiotropic effect	Epigenetic mechanism	Potential molecular response
Anti-atherosclerosis: Enhancing endothelial function	↑ histone acetylation ↑ DNA methylation upregulation of miRNAs miR-221 and miR-222 downregulation miR-34a downregulation	↑ expression of ACE2 and CCR7 ↓ TSPAN2 expression ↓ RhoA signaling ↑ blood plasma EPC counts ↑ expression of HDAC1, HDAC7, and SIRT1
Baroreceptor sensitivity enhancement	↑ DNA methylation	↓ TSPAN2 expression
Potential for anti-cancer activity	↓ DNA methylation Inhibition of HMT miR-182 upregulation miR-33b upregulation ↑ histone acetylation	↑ expression of BMP2 ↑ expression of p27 ↓ anti-apoptotic protein Bcl-2 ↓ proto-oncogene c-myc ↑ expression of p21 (tumor suppressor gene), HDAC inhibition
Increased risk for Type-2 diabetes	miRNA-33a and miRNA 33b upregulation miRNA-27 alteration upregulation of miRNA-183/96/182 cluster. downregulation of miRNA-146a	↓ ABCA1 and ABCG expression in pancreas beta cells downregulation of LDL-RNA, LRP6 and upregulation of PCSK9 ↑ expression of G6Pase and PEPCK Altered expression of PTPN1 and poor insulin signaling.

Table 1.

Summary of potential epigenetic modification induced by statins and their pleiotropic effects.

6. Conclusions

This chapter provides insights to how primary and secondary effects of statins could be mediated by epigenetic modifications, via direct and indirect mechanisms. Statins are a highly effective class of drugs used to treat hyperlipidemia, with more than 30 million users in the United State alone. Besides the lipid lowering activity of statins, it has also been demonstrated from several studies that statins have anti-inflammatory properties leading to atherosclerotic plaque stabilization and enhancement of endothelial function. These therapeutic benefits appear to decrease susceptibilities to thrombus formation and overall reduction in mortality from cardiovascular events. Overall, statin use as an adjunct to other standard-of-care drugs may have the potential to reduce cholesterol levels, induce immunomodulation, anti-inflammation, neuroprotective effects, alleviate chronic kidney disease progression, improve vascular function and bone metabolism. Despite this growing body of evidence, there is a need to quantify the pleiotropic effect of statins on specific genes or pathways to fully appreciate the use of statin as a stand-alone drug or in synergy with other drugs.

The pleiotropic effects of statins are evidenced mainly by anti-inflammatory properties which maintain a homeostatic balance between pro-inflammatory and anti-inflammatory mediators. This balance protects against the endothelial dysfunction associated with hyperlipidemia and cardiovascular disease. Overall, the pleiotropic effects of statins include: reduction of metalloproteinase production in the extracellular matrix, increased production of vasodilatory mediators like nitric oxide, inhibition of platelet aggregation, promotion of atherosclerotic plaque stabilization, enhancement of myocardial parasympathetic responsiveness, moderation of myocardial sympathovagal balance, increased myocardial perfusion, upregulation of angiogenesis, inhibition of cardiac remodeling, upregulation of baroreceptor sensitivity, downregulation of cerebral vasospasm, and reduction in expression of angiotensin II and angiotensin-1 receptor type I. The mechanisms through which statins elicit these secondary effects have been extended to the level of epigenome, albeit with little systematic investigation of epigenetic mechanisms and effects. With these promising effects of statins, this therapeutic review therefore calls for more clinical trials in human population across several cardiometabolic diseases to harness these potential benefits. Healthcare practitioners are also to be aware that the inherent ability of statins to recruit epigenetic modifications like acetylation of histones, upregulation or downregulation of micro ribonucleic acid, and methylation of DNA contribute to the pleiotropic effects of statins, while it’s not just limited to cardiovascular disease, there are potential application to various other diseases as well.

Conflict of interest

The authors declare no conflict of interest.