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Review
. 2017 Jun;174(12):1555-1569.
doi: 10.1111/bph.13704. Epub 2017 Feb 8.

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

Ioanna Andreadou  1 , Efstathios K Iliodromitis  2 , Antigone Lazou  3 , Anikó Görbe  4   5   6 , Zoltán Giricz  4   5 , Rainer Schulz  6   7 , Péter Ferdinandy  4   5   6
Affiliations
Review

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

Ioanna Andreadou et al. Br J Pharmacol. 2017 Jun.

Abstract

Hypercholesterolaemia 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 hypercholesterolaemia affects the global cardiac gene expression profile, among many other factors, it results in increased myocardial oxidative stress, mitochondrial dysfunction and inflammation triggered apoptosis, all of which may account for myocardial dysfunction and increased susceptibility of the myocardium to infarction. In addition, numerous experimental and clinical studies have revealed that hyperlcholesterolaemia may interfere with the cardioprotective potential of conditioning mechanisms. Although not fully elucidated, the underlying mechanisms for the lost cardioprotection in hypercholesterolaemic animals have been reported to involve dysregulation of the endothelial NOS-cGMP, reperfusion injury salvage kinase, peroxynitrite-MMP2 signalling pathways, modulation of ATP-sensitive potassium channels and apoptotic pathways. In this review article, we summarize the current knowledge on the effect of hypercholesterolaemia on the non-ischaemic and ischaemic heart as well as on the cardioprotection induced by drugs or ischaemic preconditioning, postconditioning and remote conditioning. Future perspectives concerning the mechanisms and the design of preclinical and clinical trials are highlighted.

Linked articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.

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Figures

Figure 1
Figure 1
Effect of hypercholesterolaemia on major known cardioprotective cellular mechanisms induced by conditioning interventions: Hypercholesterolaemia inhibits the phosphorylation of Akt and impairs the myocardial NO‐cGMP pathway leading to inhibition of mitochondrial KATP channel opening. Additionally, impairment of the inhibition of GSK3β may cause excessive opening of the mPTP leading to mitochondrial swelling and cell death. Hypercholesterolaemia also inhibits the phosphorylation of extracellular‐ERK1/2 and induces down‐regulation of HIF‐1α, which is one of the cardioprotective mechanisms of PostC. Hypercholesterolaemia produces excessive apoptosis by down‐regulating Bcl‐2 and up‐regulating Bcl‐2‐like protein 4 (Bax), cytochrome c, caspase 9 and caspase 3. Hypercholesterolaemia inhibits mitochondrial translocation of connexin 43 (Cx43). Hypercholesterolaemia produces an increased generation of superoxide anion and a decreased bioavailability of NO through, for example, eNOS and iNOS uncoupling by a reduction in the NOS cofactor BH4. Therefore, during hypercholesterolaemia, an increased formation of peroxynitrite, a toxic reaction product of superoxide and NO, is observed that further depletes bioavailability of NO in the heart. Moreover, the inhibition of oxidative activation of MMP2 by conditioning is blocked in hypercholesterolaemia due to peroxynitrite‐induced activation of MMP2. Green boxes and dashed arrows denote major cardioprotective pathways that are affected by hypercholesterolaemia. Orange boxes and arrows indicate major influence of hypercholesterolaemia on cardioprotective cellular pathways.
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