The purpose of this review is to summarize recent reports on the role of HDL (High Density Lipoprotein) and apolipoprotein A-I (apoA-I) mimetics in protection against atherosclerosis. HDL and HDL mimetic peptides continue to demonstrate beneficial effects in preclinical studies. HDL-cholesterol is only a minor part of the HDL particle and the reason HDL levels are expressed as HDL-cholesterol is the simplicity of measurement of the cholesterol associated with HDL particle. In addition, the composition of HDL, its function and protective capacity is not reflected by its cholesterol content. Several major studies have shown that simply increasing the amount of circulating HDL-cholesterol does not reduce the risk of coronary heart disease (CHD) events, CHD deaths, or total mortality. HDL-cholesterol does not define the lipids and the proteins associated with HDL and the HDL-proteome can be just a mediator or a marker of CHD. The efficacy of apolipoprotein A-I (apoA-I) in preliminary human studies and in improving atherosclerosis in animal models makes it an attractive therapeutic candidate. However, it has 243 amino acid residues, necessitating it to be given intravenously and making it difficult and expensive to synthesize. ApoA-I is a selective target for myeloperoxidase-catalyzed oxidation, which results in impairment of the ability of HDL to promote cholesterol efflux. HDL could be a therapeutic target by modifying its protein and lipid cargo to improve its anti-inflammatory properties. Treatment with apolipoprotein mimetic peptides is among the methods that can modify the lipid and protein cargo of HDL. In summary one reason for the failure of the new compounds that increased HDL-cholesterol levels but did not reduce coronary events could be interference in the function of cholesterol ester transfer protein (CETP). An additional reason could be that the composition and the function of HDL was not the focus of the studies. Mere increase of HDL-cholesterol might not always be sufficient and there is a need to increase the level of HDL molecules that actually protect against atherosclerosis.
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