Individual contributions of HDL-C, non-HDL-C, and apoE to atherosclerosis regression and to the migratory and inflammatory properties of plaque monocyte-derived (CD68+) cells

• Applicant: Dr. Bernd Hewing
• Subject Area: Cardiology, Angiology
• Term: from 2010 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 170683487

Recent discoveries have increased the understanding of atherosclerosis regression and have encouraged optimism about its clinical feasibility1. A novel transplant model of mouse atherosclerosis regression has been developed in which diseased plaque-containing aortic segments from apoE-deficient mice (apoE-/-; a standard mouse model of human atherosclerosis) were placed into normolipidemic wild type (WT) recipients. Once in the WT environment, diseased aortic segments displayed a regression process marked by remarkable and rapid loss of CD68+ cells (primarily macrophages and foam cells) through the induction of an emigration process. The loss of CD68+ cells was dependent on the chemokine receptor CCR72,3. In addition to acquiring a migratory phenotype, regressing plaque CD68+ cells also became enriched in markers of the M2 anti-inflammatory state and depleted in those associated with the inflammatory M1 macrophage state. There are 3 major changes in the plasma environment when plaques are transferred from apoE-/- to WT mice: 1) the normalization of HDL cholesterol (HDL-C); 2) the lowering of non-HDL-C; 3) and an increase of apoE. It can be hypothesized that each change contributes to atherosclerosis regression, as defined by a loss of plaque CD68+ cells, and to the regulation of multiple molecular changes in these cells. The goal of this study is to determine the individual contributions of HDL-C, non-HDL-C, and apoE to atherosclerosis regression and to the migratory and inflammatory properties of plaque monocyte-derived (CD68+) cells. These studies are relevant to the current clinical controversy on the relative importance of LDL-C and HDL-C to cardiovascular disease risk and to new strategies to regress plaques.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Edward A. Fisher