Statins: Epidrugs with effects on endothelial health?

Abstract

Background: Epigenetic events involving the methylation of CpG cites in DNA, histone modifications and noncoding RNAs correlated with many essential processes in human cells and diseases, such as cancer and cardiovascular diseases. HMG-CoA reductase inhibitors (statins)-the LDL cholesterol-lowering drugs-are broadly used in cardio-and cerebro-vascular diseases. It is well established that statins exert pleiotropic functions, but how they exert effects on epigenetic modifications independently of HMG-CoA reductase inhibition is not yet clear. Thereby, understanding these mechanisms may pave the way for further clinical application of statin therapy. Design: Following and electronic database search, studies reporting substantial effects of statins on epigenetic reprogramming in both cultured cells and in vivo models were retrieved and reviewed. Results: Epigenetic mechanisms play an essential role in cellular development and function, and data collected in the past few years have revealed that many of the pleiotropic properties of statins are mediated by epigenetic mechanisms. Furthermore, those 'nonclassical' effects are not limited to CV field but they would extend to other conditions such as malignancies. Conclusion: This review suggests that the epigenetic effects of statins mediate, at least in part, the pleiotropic actions of these drugs but further validation of such effects in clinical studies is yet to be provided.

Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment

“…Lipid-lowering therapies, including 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (i.e., statins) and proprotein convertase subtilisin/kexin type 9 inhibitors, reduce circulating levels of LDL-cholesterol and thus oxLDL in the vessel wall, and decrease the incidence of severe events in CVD ( Silverman et al, 2016 ; Mach et al, 2020 ), although these agents are not sufficient to prevent plaque formation ( Tran-Dinh et al, 2013 ; Moss and Ramji, 2016 ). Moreover, a spectrum of anti-atherogenic effects of statins on the endothelium has been previously discussed in detail ( Xu et al, 2021 ), and includes reduced inflammation through NF-κB blockade ( Greenwood and Mason, 2007 ), inhibition of EC apoptosis via Janus kinase 2/signal transducer and activator of transcription 3 signaling ( Wang K. et al, 2020 ), protection against EndMT via Kruppel-like factor 4/miR-483 ( He et al, 2017 ), epigenetic modulation of ECs through histone modification ( Mohammadzadeh et al, 2020 ), and increased NO production via hydrogen sulfide and eNOS ( Citi et al, 2021 ; Xu et al, 2021 ). Notably, the statin-mediated mechanisms that contribute to elevated eNOS activity include increased eNOS transcription via KLF2 ( Parmar et al, 2005 ), improved eNOS mRNA stability via polyadenylation ( Kosmidou et al, 2007 ), and increased eNOS phosphorylation via phosphatidylinositol 3-kinase/Akt signaling ( Kureishi et al, 2000 ).…”

Updating concepts on atherosclerotic inflammation: From pathophysiology to treatment

“…Noteworthy, some commonly used drugs with pleiotropic activity-that is, statins-are increasingly recognized as potential epigenetic drugs. 116…”

Statins: a repurposed drug to fight cancer

“…However, in the past, studies have shown that statins exhibit pleiotropic effects independent of their lipid-lowering properties. It has been reported that the epigenetic effects of statins mediate these pleiotropic effects, at least to some extent [ 4 ]. Among them, the anti-tumor properties of statins have attracted particular attention.…”