Statins in Atherosclerosis: Comparison
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Despite increased public health awareness, atherosclerosis remains a leading cause of mortality worldwide. Significant variations in response to statin treatment have been noted among different populations suggesting that the efficacy of statins may be altered by both genetic and environmental factors. The existing literature suggests that certain long noncoding RNAs (lncRNAs) might be up- or downregulated among patients with atherosclerosis. LncRNA may act on multiple levels (cholesterol homeostasis, vascular inflammation, and plaque destabilization) and exert atheroprotective or atherogenic effects.

  • statin
  • RNA
  • epigenetics
  • vascular biology

1. Statins and LncRNAs: Current Evidence

Although treatment with statin represents the main therapeutic strategy against hyperlipidemia and atherosclerosis, there are significant variations in treatment response among different populations [1][40]. The inter-individual variation in response to statin treatment remains a concern, and the underlying mechanism is not completely understood [1][2][40,41]. To date, it is recognized that apart from environmental factors, genetic alterations may also be implicated in the varied efficacy of statins in regulating cholesterol metabolism [1][2][3][40,41,42]. Nevertheless, only a few studies have investigated the interplay between statins and lncRNAs known to be implicated in atherosclerosis [4][5][6][7][8][9][10][11][12][13,22,23,43,44,45,46,47,48].

1.1. Cholesterol Homeostasis

Mitchel and colleagues first showed that simvastatin-induced expression of lncRNA RP1-13D10.2 in lymphoblastoid cell lines was higher in high versus low responders [7][43]. In addition, the study showed that RP1-13D10.2 increased LDLR expression and stimulated LDL uptake in Huh7 and HepG2 cell lines from participants of the Cholesterol and Pharmacogenetics simvastatin clinical trial, suggesting that lncRNAs could potentially contribute to the inter-individual variation in statin response [7][43]. Another study demonstrated that atorvastatin increased the expression of lncRNA LASER in a dose-dependent manner in HepG2 cells and peripheral blood of patients (patients with no previous statin use that were started on atorvastatin 20 mg/day/5 days) which was accompanied by an increase in PCSK9 both in humans as well as an in vitro model of HepG2 cells [4][13]. Since PCSK9 has been reported to promote degradation of LDLR [13][49], this suggested feedback regulation of cholesterol on LASER expression [4][13]. In contrast to this study, Paez et al. reported that treatment with atorvastatin (20 mg/day/4 weeks) among hypercholesterolemic patients resulted in increased expression of two lncRNAs in peripheral blood samples by RT-qPCR, ARSR and CHROME, but not LASER, among hypercholesterolemic patients, suggesting that statins may differentially regulate the expression of certain lncRNAs [8][44]. Although a clear explanation for these disparate results does not exist, differences in the duration of treatment (5 days vs. 4 weeks) and the target populations (patients not on statins who started statins for 5 days vs. hypercholesterolemic patients who received statins for 4 weeks) might have accounted for the variations in lncRNA expression with atorvastatin treatment.

1.2. Vascular Inflammation

Furthermore, Su et al. reported that treatment with atorvastatin inhibited the expression of lncRNA MEG3 in a hypoxia-induced cardiac progenitor cell (CPC) model [9][45]. Given that hypoxia inhibits CPC viability and proliferation through modulating MEG3 expression, inhibition of the MEG3/miR22 pathway might be a potential mechanism and target for the development of effective drugs for myocardial repair following myocardial infarction [9][45]. In another study, atorvastatin was shown to enhance the therapeutic efficacy of mesenchymal stem-cell derived exosomes (MSCATV-Exo) in a rat model of acute myocardial infarction through upregulation of the lncRNA H19 [10][46]. In fact, silencing lncRNA H19 abolished the cardioprotective effects of exosomes, suggesting that this lncRNA might be, at least in part, responsible for the cardioprotective effect of MSCATV-Exo on infarcted hearts [10][46]. Wu et al. also demonstrated atorvastatin inhibited pyroptosis via inducing expression of lncRNA NEXN-AS1, suggesting an additional atheroprotective mechanism for statins [5][22].

More recently, statins have been shown to exert their atheroprotective effects through regulation of the lncRNA MANTIS [14][6][11,23]. Indeed, Leisegang et al. showed that certain statins (i.e., cerivastatin, fluvastatin, simvastatin, and atorvastatin) induced the expression of lncRNA MANTIS in both human and cultured endothelial cells. MANTIS had an inhibitory effect on ICAM-1 [14][11], which is involved in the transendothelial migration of leukocytes to the sites of inflammation [15][50]. In addition, MANTIS mediated several statin-induced responses, such as regulation of angiogenesis, proliferation, and telomerase activity, to promote endothelial quiescence and vascular protection [14][11]. Apart from MANTIS, statins also induced lncRNA LISPR1 and SIPR1, resulting in an increased angiogenic capacity required for normal endothelial cell function [11][47]. Last but not least, a clinical study [16][51] demonstrated that lncRNA AWPPH—an lncRNA associated with poor prognosis of hepatocellular carcinoma—was highly expressed in patients with coronary artery disease (CAD) when compared with healthy individuals, while it was reduced after treatment with rosuvastatin and atorvastatin, suggesting that AWPPH could be a potential marker to predict outcomes of patients with CAD [12][48].

Collectively, accumulating evidence has demonstrated that lncRNAs may be implicated in the pleiotropic effects of statins. Despite efforts in identifying the molecular mechanisms of statin treatment, there are only limited data on statins and vascular epigenetics. As such, the present review aimed to summarize the available studies in the field so that investigators can build on this previous work and work towards enhancing our understanding around the mechanisms by which statins exert their pleiotropic effects at the molecular level [17][52].

2. Regulation of LncRNA and Determinants of Statin Efficacy

While the underlying mechanisms of variations in statin response are not completely understood, the association of certain lncRNAs with currently accepted determinants of statin efficacy (i.e., gene polymorphisms, P450 enzyme, efflux and uptake transporters) provides a rationale for further research into how lncRNA regulation might be associated with response to statins. Although only a few studies have directly examined the association of certain statins together with lncRNAs and determinants of statin efficacy to date, the association of the latter two has been more frequently reported.

LncRNAs have emerged as critical players in cellular cholesterol metabolism. Previous studies have reported on the role of lncRNAs LASER, LeXis, MeXis, GAS5, and CHROME in cholesterol metabolism (cholesterol efflux, synthesis etc.) and have been reviewed above [4][18][19][20][21][22][13,15,16,18,19,20]. Cai et al. also reported that overexpression lncRNA ENST00000602558.1 downregulated ABCG1 mRNA and protein expression in VSMCs, leading to decreased ABCG1-mediated cholesterol efflux and increased lipid accumulation [23][53]. This process might promote VSMC phenotype switching to foam cells, a major mechanism of atherosclerosis [24][54]. Similarly, Tang et al. also reported that lncRNA ZFAS1 was upregulated in an in vitro model of atherosclerosis (THP-1 macrophage-derived foam cells). Overexpression of ZFAS1 promoted inflammatory responses and decreased cholesterol efflux by upregulating ADAM10/RAB22A expression [25][55].

In a separate study, Lan et al. identified an lncRNA named lnc-HC that negatively regulated cholesterol metabolism in hepatocytes of an experimental metabolic syndrome rat model [26][56]. By binding to hnRNPA2B1, the lnc-HC–hnRNPA2B1 complex decreased Cyp7a1 or Abca1 (both on mRNA and protein levels)—both of which are implicated in cellular cholesterol excretion—thus augmenting cholesterol accumulation within hepatocytes [26][56]. Given that the abovementioned lncRNAs were shown to be important regulators of cholesterol efflux and metabolism, these lncRNAs may represent targets to increase statin efficacy in nonresponders.

In addition, certain lncRNAs have been found to regulate cytochrome P450 [27][57], and since most statins are metabolized through cytochrome P450, further research is needed to investigate whether certain lncRNAs might be targets for enhancing the response in statin nonresponders.

Genome-wide studies have also demonstrated that combination of certain polymorphisms might be important predictors of statin response [28][58]. Polymorphisms in lncRNAs have recently been associated with increased risk of cardiovascular events. In particular, Zheng et al. demonstrated that a deletion polymorphism (rs145204276) in the promoter of lncRNA GAS5—implicated in cholesterol efflux and metabolism as noted above [21][19]—was related to an increased risk of ischemic stroke in humans [29][59]. Similarly, polymorphisms in lncRNA MEG3 (i.e., rs7158663 and rs4081134) were associated with increased risk of ischemic stroke jointly with polymorphisms in miR-181b rs322931 [30][60]. In a case–control study, a single nucleotide polymorphism rs4977574 of CDKN2BAS was shown to be a risk factor for coronary heart disease in both females and males under the age of 65 [31][61]. These results were confirmed in a meta-analysis of 36,452 cases and 39,781 controls which showed that patients with the polymorphism rs4977574 had 27% higher odds of coronary heart disease (OR = 1.27, 95%CI 1.22–1.31) compared with their counterparts [31][61]. Another case–control study from Pakistan revealed a strong association of polymorphism rs1333049:C > G of lncRNA ANRIL with myocardial infarction [32][62]. Finally, Li et al. demonstrated that polymorphisms rs9632884 of lncRNA ANRIL and rs3200401 of lncRNA MALAT1 were significantly associated with increased cholesterol and triglyceride levels among both healthy and myocardial infarction patients without necessarily being associated with an increased risk of myocardial infarction [33][63]. Collectively, given the association of certain lncRNA polymorphisms with a higher frequency of adverse events as well as lipid levels, variations in statin efficacy might be associated with certain lncRNA and other gene polymorphisms.

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