High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies

Abstract

High-density lipoprotein (HDL) particles transport (among other molecules) cholesterol (HDL-C). In epidemiological studies, plasma HDL-C levels have an inverse relationship to the risk of atherosclerotic cardiovascular disease. It has been assumed that this reflects the protective functions of HDL, which include their ability to promote cholesterol efflux. Yet, several recent pharmacological and genetic studies have failed to demonstrate that increased plasma levels of HDL-C resulted in decreased cardiovascular disease risk, giving rise to a controversy regarding whether plasma levels of HDL-C reflect HDL function, or that HDL is even as protective as assumed. The evidence from preclinical and (limited) clinical studies shows that HDL can promote the regression of atherosclerosis when the levels of functional particles are increased from endogenous or exogenous sources. The data show that regression results from a combination of reduced plaque lipid and macrophage contents, as well as from a reduction in its inflammatory state. Although more research will be needed regarding basic mechanisms and to establish that these changes translate clinically to reduced cardiovascular disease events, that HDL can regress plaques suggests that the recent trial failures do not eliminate HDL from consideration as an atheroprotective agent but rather emphasizes the important distinction between HDL function and plasma levels of HDL-C.

Keywords: atherosclerosis; cholesterol, HDL; coronary artery disease; mice; regression.

Figure 1. The promotion of atherosclerosis regression by HDL in an aortic transplantation mouse model

Monocytes are recruited into plaques and become macrophages. These macrophages become activated, cholesterol-laden foam cells, as a result of ingesting normal and modified apoB-containing lipoproteins, and are retained in the plaque. Based on in vitro and pre-clinical studies, recently recognized ways in which HDL can contribute to plaque regression include 1) reduced monocyte recruitment because of reduced leukocytosis or endothelial cell adhesion molecule expression, 2) the stimulation of CCR7 expression by the promotion of cholesterol efflux from foam cells, which results in emigration of macrophages to lymphoid tissue and to the systemic circulation, and, 3) the stimulation of the STAT6 pathway to polarize macrophages to the M2 state, as indicated by the increase in the markers mannose receptor (MR), IL-10, and arginase I (Arg I). As tissue repair cells, M2 macrophages also exhibit enhanced efferocytosis (disposal) of apoptotic cells. See text for details and for additional mechanisms.