Pleiotropic and Adverse Effects of Statins—Do Epigenetics Play a Role?

Abstract

Statins are widely used to prevent major cardiovascular events by lowering serum cholesterol. There is evidence that statins have pleiotropic effects-that is, cholesterol-independent effects-that may also confer protection from cardiovascular disease and potentially numerous other pathologies, including cancer. Statins also have a number of well described adverse effects, including myopathy, rhabdomyolysis, liver damage, and type 2 diabetes. This paper examines the evidence of epigenetic modifications as a contributory factor to the pleiotropic and adverse effects of statins. In vitro and animal studies have shown that statins can inhibit histone deacetylase activity and increase histone acetylation. Similarly, there is evidence that statins may inhibit both histone and DNA methyltransferases and subsequently demethylate histone residues and DNA, respectively. These changes have been shown to alter expression of various genes, including tumor suppressor genes and genes thought to have anti-atherosclerotic actions. Statins have also been shown to influence the expression of numerous microRNAs that suppress the translation of proteins involved in tumorigenesis and vascular function. Whether the adverse effects of statins may also have an epigenetic component has been less widely studied, although there is evidence that microRNA expression may be altered in statin-induced muscle and liver damage. As epigenetics and microRNAs influence gene expression, these changes could contribute to the pleiotropic and adverse effects of statins and have long-lasting effects on the health of statin users.

Statin‐dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content

“…Statins that specifically target the HMG-CoA reductase inhibiting de novo Chol synthesis also display pleiotropic effects (36,37). Statins have been reported to alter mitochondrial function in skeletal muscle (38,39), but the information available regarding the effects on mitochondria in cancer cells is scarce (40).…”

Cholesterol intake and statin use regulate neuronal G protein-gated inwardly rectifying potassium channels

“…The activity levels of GIRK channels following a high-cholesterol diet supplemented with atorvastatin therapy were not significantly different from those recorded in neurons freshly isolated from rats on a control, standard rodent food. This key finding is critical considering the widely reported pleiotropic statin effects that extend beyond lowering cholesterol levels (23)(24)(25)(26)75). Notably, it has been previously shown that statin therapy did not affect the intrinsic membrane properties of hippocampal pyramidal neurons (76,77).…”

Network Medicine: A Clinical Approach for Precision Medicine and Personalized Therapy in Coronary Heart Disease

“…Furthermore, the pleiotropic effects of these therapeutic compounds may depend, in part, on their epigenetic effects, since they can inhibit HDAC activity 98) . The protective effect of statins for primary prevention has also been demonstrated in three large clinical studies: the MEGA, the JUPITER and HOPE-3 [99][100][101][102] . Another clinical trial for primary prevention investigated fenofibrate treatment, in combination with atorvastatin, to test the efficacy and safety of once daily fenofibrate assumption on cIMT detected by US in dyslipidemic patients with optimal levels of low density lipoprotein cholesterol after atorvastatin treatment.…”