Statins: Pleiotropic Regulators of Cardiovascular Redox State

Abstract

Lipid-lowering treatment with statins is one of the most effective therapeutic strategies in cardiovascular medicine because they reduce cardiovascular risk in both primary and secondary prevention. Despite the wellestablished links between low-density lipoprotein and cardiovascular risk, the clinical benefit from statin treatment is not fully explained by their lipid-lowering potential. A number of pleiotropic effects of statins have been described over the past decade, and their ability to suppress global oxidative stress is probably one of the most important mechanisms by which they exert their beneficial effects on the cardiovascular system. In this Forum, there are review articles discussing the molecular mechanisms by which statins modify redox signaling in the vasculature and the heart. They exert direct effects on the vascular wall and the myocardium or indirect by targeting the interactions between the cardiovascular system and adipose tissue or circulating cell types. The review articles in this Forum follow a translational approach and link the molecular mechanisms by which statins modify cardiovascular redox signaling with their clinical benefit in the prevention and treatment of cardiovascular diseases. Antioxid. Redox Signal. 20, 1195-1197. When the first HMG-CoA-reductase inhibitor was developed in the 1970s (i.e., mevastatin), nobody could imagine that this pharmacological intervention would have such an enormous impact in clinical practice across so many different medical fields. This new inhibitor took more than a decade to attract the attention of pharmaceutical industry and led to the development of lovastatin, the first registered statin for clinical use. Since then, statins came to the forefront of cardiovascular pharmacology, and it is now clear that by inhibiting HMG-CoA-reductase and reducing low-density lipoprotein (LDL), they are able to lower cardiovascular risk in both primary and secondary prevention.Over the past decade, it became clear that statins exert cardiovascular effects beyond lipid lowering, and these were called ''pleiotropic effects.'' One of the most important aspects of statin treatment is their ability to reduce oxidative stress in various tissue and cell types in the cardiovascular system, and this is believed to be a key mechanism by which they reduce cardiovascular risk. Indeed, oxidative stress is a critical therapeutic target in cardiovascular pharmacology as it is involved in atherogenesis, arrhythmogenesis, and other cardiovascular disorders. In this Forum of ARS, experts in the field of statin pharmacology present the most up-to-date knowledge on the role of statins in the regulation of cardiovascular redox signaling and give their expert opinion on the future potential of statin treatment in cardiovascular science.In the first article of this Forum, Margaritis et al. (6) discuss the role of statins as regulators of redox signaling in the human vascular endothelium (Fig. 1). They provide a comprehensive review of the role of oxidative stress in vascula...

Effect of hypercholesterolaemia on myocardial function, ischaemia–reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

“…In fact, experimental and clinical studies have shown that statins are involved in a reduction in reperfusion injury and inflammatory reactions and in the improvement in the microcirculation. Statins are implicated in the generation of intracellular mediators, which may prevent mPTP opening and therefore preserve mitochondrial integrity and the survival of cells (Ludman et al ., ; Antoniades and Channon, ; Mihos et al ., ). However, a growing body of evidence suggests that the cardioprotective potential of statins, associated with their pleiotropic and anti‐inflammatory effects, is mediated by the up‐regulation and activation of PPARα (Balakumar and Mahadevan ; Ravingerova et al ., ).…”

The Role of Oxidative Stress in Physiopathology and Pharmacological Treatment with Pro- and Antioxidant Properties in Chronic Diseases

“…Statins show pleiotropic effects on endothelial function, inhibition of thrombus gene activity, the stability of atherosclerosis plaques, and decreased inflammation and OS [ 36 ]. Statins have been shown to have antioxidant effects on redox signaling of vascular and myocardial tissue by modifying NADPH oxidase activity [ 37 ]. Statins show effects on eNOS and decreased LPO [ 38 ].…”

Perivascular Adipose Tissue as an Endocrine Organ: The Role of Statins

“…Cholesterol lowering-independent effects have been reported to contribute to the beneficial effects of statins on the cardiovascular system. These effects have been named "pleiotropic"; this term refers to all anti-inflammatory (42,43) and anti-oxidant (42,(44)(45)(46) properties attributed to the use of statins via mechanisms other than their cholesterol-lowering actions. Given the role of PVAT in regulating vascular homeostasis, it is rational to hypothesize that at least some of the beneficial effects of statins may be mediated by direct actions on PVAT.…”