Synthetic high density lipoproteins for the treatment of myocardial ischemia/reperfusion injury

Abstract

Synthetic high density lipoproteins (sHDL) are discoidal lipoprotein particles made of an apolipoprotein and a phospholipid, which mimic most, if not all, of the atheroprotective properties of plasma HDL, including stimulation of reverse cholesterol transport (RCT), prevention of endothelial dysfunction, and inhibition of lipid oxidation. sHDL are currently under development as a novel treatment for atherosclerotic cardiovascular disease. A number of preclinical studies have demonstrated the ability of single or multiple injections of sHDL to induce the regression of atherosclerotic plaques and prevent arterial restenosis. In the first phase II trial in patients with acute coronary syndromes, a short-term treatment with sHDL containing the disulfide-linked dimer of the apolipoprotein A-I_Milano variant (A-I_M/A-I_M) caused a remarkable reduction of atheroma volume. sHDL also display a direct cardioprotective activity in ex vivo and in vivo models of myocardial ischemia/reperfusion (I/R) injury, and may become a useful adjunctive therapy to improve clinical outcomes in patients with acute coronary syndromes or undergoing coronary procedures.

Introduction

Several prospective studies have clearly established that plasma high density lipoprotein (HDL) cholesterol levels are inversely related to the incidence of coronary heart disease (CHD) and are a powerful predictor of future coronary events; even small increases in HDL-cholesterol translate into substantial CHD risk reductions (Franceschini, 2001). HDL are not simply markers of CHD risk, because several lines of evidence indicate a cause–effect relationship between low plasma HDL levels and development of CHD. Studies in animal models have established that interventions which raise the level of HDL cholesterol, by, for example, overexpression of apolipoprotein A-I (apoA-I), the major protein component of human HDL, reduce the extent of atherosclerosis (Paszty et al., 1994). In vitro and in vivo experiments provide mechanistic explanations for the atheroprotective effects of HDL, which include stimulation of cholesterol removal from the arterial wall, prevention of endothelial dysfunction, reduction of oxidative stress (Nofer et al., 2002). Finally, there is limited but compelling clinical trial evidence that coronary event rates may be reduced by treatments that raise plasma HDL levels (Frick et al., 1987, Rubins et al., 1999). These studies are all consistent with the view that HDL may be a therapeutic target for further reducing CHD burden in the therapeutic era dominated by the statins, which lower plasma low density lipoproteins (LDL). Indeed, several strategies have recently emerged to treat cardiovascular disease through increased HDL-mediated atheroprotection. These range from the administration of small orally active molecules, which raise plasma HDL levels by affecting the expression or function of one of the many factors regulating HDL metabolism, to the direct infusion of HDL mimetics (Linsel-Nitschke & Tall, 2005).

Early studies have shown that, besides being a strong independent predictor of the occurrence of primary coronary events, a low plasma HDL cholesterol level is also associated with long-term unfavorable prognosis in patients who have recovered from a myocardial infarction (Berge et al., 1982, Miller et al., 1992). More recent evidence indicates that an inverse relationship also exists between plasma HDL cholesterol at the time of an acute coronary event and the 16-week risk of recurrent events (Olsson et al., 2005). This association probably does not reflect accelerated atherogenesis in the low-HDL patients but suggests a direct detrimental effect of low HDL on postischemic myocardial function. Indeed, a low HDL level adversely influences postinfarct left ventricular function in patients with myocardial infarction, independent of the severity of coronary atherosclerosis (Kempen et al., 1987, Wang et al., 1998b), and is an independent predictor of left ventricular dysfunction in angina patients with normal coronary angiograms (Wang et al., 1999). These observations raise the possibility that HDL might be an attractive target, not only for reducing long-term CHD risk, but also for modifying the short-term high-risk state following an acute coronary syndrome. We hypothesize that such objective could be achieved through the infusion of HDL mimetics. This review will focus on 3 aspects of HDL biology and pharmacology: the structural and functional properties of plasma HDL; the development of synthetic high density lipoproteins (sHDL) as therapeutic agent; and the ability of sHDL to exert direct cardioprotective effects ex vivo and in vivo. In order to understand the potential of sHDL in the therapeutic environment it is necessary to describe HDL structure, metabolism and role in atherogenesis in some detail.