Interplay of proteins involved in atherosclerosis - dependence of apolipoprotein AI on ABC-cholesterol transporters to exert its atheroprotective function

Atherosclerotic changes in the vessel walls leading to myocardial infarct, stroke and other diseases of the circulatory system is the most common cause of death in western civilization and further gains ground around the globe. Conversion of macrophages into cholesterol laden foam cells contributes to atherosclerotic lesion development. For the removal of excess cholesterol macrophages depend on extracellular acceptors. The ATP binding cassette transporters (ABC-transporter) A1 (ABCA1) and G1 (ABCG1) were shown to mediate cholesterol efflux from macrophages to lipid free apoAI and HDL, respectively, implying an atheroprotective role for both transporters. In vivo studies on macrophage specific ABCA1 and ABCG1 knock out mice supported this but were not completely conclusive. However, a recent study showed macrophages specific double deficiency of ABCA1 and ABCG1 resulting in markedly increased atherosclerosis development, a high infiltration of vessel walls with lipid loaded macrophages and concluded that ABCA1 and ABCG1 are working in concert reflecting the importance of the expression of both transporters in macrophages for the maintenance of sterol removal. Apolipoprotein AI, the main protein of HDL particles posses the ability to efficiently protect from atherogenesis and to even decrease already existing lipid depositions, as shown by studies with human apoAI transgenic animals. Furthermore, it is a well documented fact that that plasma HDL cholesterol levels correlate inversely with the incidence of atherosclerotic cardiovascular disease. The mechanism by which apoAI/HDL exerts its atheroprotective role is thought to be mainly due to enhanced cholesterol efflux from arterial macrophages initiated by lipid poor apoAI and extended by nascent and mature HDL particles, involving ABCA1 and ABCG1, which displays the first step of a process called reverse cholesterol transport resulting in the uptake of sterol by the liver and excretion into the bile. However this has never been proven and apoAI/HDL have also other reported atheroprotective properties, like protection of other lipoproteins from oxidation, inhibition of inflammation and reduction of thrombotic events. Therefore, the question that will be addressed in this proposal is: How important is sterol removal from macrophages by apoAI/HDL in relation to other protective factor exerted by apoAI/HDL regarding its protective role in atherogenesis. This question will be addressed by performing transplantations of bone marrow from either wild type, ABCA1 deficient, ABCG1 deficient or ABCA1 ABCG1 double deficient mice into LDL receptor deficient, hyperlipidemic, recipient mice, which will in addition carry the human apoAI transgene. Transgenic animals will have elevated apoAI levels and more human like HDL subpopulations. The expected outcome is that upon deletion of both ABC cholesterol transporters apoAIs atheroprotective effect is substantially decreased resulting in elevated atherosclerosis even in the presence of the apoAI transgene. This study will help to understand and to set into proportion the importance of cholesterol removal and other beneficiary properties exerted by apoAI/HDL.