CARDIOPROTECTION BY HIGH DENSITY LIPOPROTEIN IS MEDIATED BY THE SCAVENGER RECEPTOR CLASS B TYPE 1

Abstract

Cardiovascular disease and cancer are the leading causes of death in Canada and are a major burden to the health of developed societies. Three quarters of all cardiovascular related deaths are due to ischemic heart disease and heart attack. Doxorubicin is an effective and commonly used chemotherapeutic that has deleterious side effects including cardiotoxicity and heart failure, thereby limiting its long term use. In a recent study both reconstituted and native high density lipoprotein particles provided protection against doxorubicin-induced cell death in vitro, and a number of studies have implicated high density lipoprotein in protection against myocardial ischemia. As high density lipoprotein provides protection to cardiomyocytes undergoing cardiotoxic stress, or ischemic stress, we postulate that it may be a notable target for protection against the deleterious effects of cardiac stress. The scavenger receptor class B type I is a high-affinity high density lipoprotein receptor, and its role in facilitating high density lipoprotein mediated signaling in the cardiomyocyte has yet to be assessed. Here we have evaluated whether increasing high density lipoprotein protects cardiomyocytes and the heart against cardiotoxic or ischemic stress, and the signaling mechanisms involved. We have shown that increasing plasma high density lipoprotein attenuates the cardiotoxic effects of doxorubicin, and that high density lipoprotein protects isolated cardiomyocytes against necrosis induced by simulated ischemia. Our findings presented here demonstrate a critical role for cardiomyocyte scavenger receptor class B type 1 in facilitating high density lipoprotein mediated protection. We have also identified phosphoinositide 3-kinase and protein kinase B as downstream mediators in the cardioprotective signaling cascade by high density lipoprotein and the scavenger receptor class B type I.