Effect of hypercholesterolemia on myocardial function, ischemia-reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

Abstract

Hypercholesterolemia is considered to be a principle risk factor for cardiovascular disease, having direct negative effects on the myocardium itself, in addition to the development of atherosclerosis. Since hypercholesterolemia affects global cardiac gene expression profile, among many other factors, increased myocardial oxidative stress, mitochondrial dysfunction and inflammation trigger apoptosis and this may account for myocardial dysfunction and increased susceptibility of the myocardium to infarction. In addition, numerous experimental and clinical studies revealed that hyperlcholesterolemia may interfere with the cardioprotective potential of conditioning mechanisms. Although not fully elucidated, the underlying mechanisms for the lost cardioprotection in hypercholesterolemic animals have been reported to involve dysregulation of eNOS-cGMP, RISK, peroxynitrite-MMP2 signaling pathways, modulation of KATP channels and apoptotic pathways. In this review article, we summarize current knowledge on the effect of hypercholesterolemia on the non-ischemic and ischemic heart as well as on the cardioprotection induced by drugs or ischemic preconditioning (PC), postconditioning (PostC) and remote conditioning. We also summarize the effects of hypercholesterolemia on drug-induced cardioprotection, in the presence of hypercholesterolemia. Future perspectives concerning the mechanisms and the design of pre-clinical and clinical trials are highlighted.