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
Final Report Abstract
The present research led to three different models for regression of atherosclerosis - aortic arch transplant model (project 1), ApoA-I injection model (project 2), MTP inhibitor regression model (project 3) – which are based on different manipulations of the lipid environment. In project 1 the aortic arch transplant model was used to evaluate the impact of chemokine receptor CCR7, previously shown to be an important regression factor, in HDL-mediated regression of atherosclerosis (by using apoE/CCR7 double knock-out mice as aortic arch donors and apoE knock-out mice transgenic for human apoA-I as transplant recipients). Notably, ApoE/CCR7 double knock-out mice had attenuated development of atherosclerosis, indicating an atheroprotective role of CCR7 in the progression phase. However, after transplantation regression of atherosclerosis was significantly impaired in the apoE/CCR7 knock-out mice compared to regular apoE knock-out mice. Therefore, we conclude that CCR7 is a crucial factor for HDL-mediated regression. In project 2 regression of atherosclerosis was achieved by the injection of ApoA-I, the major protein of HDL. Increased levels of myeloperoxidase-modified HDL have been described in patients with coronary artery disease. In our study we have shown that modification of ApoA-I by MPO impairs the particle’s ability to induce regression of atherosclerosis. These findings underline the importance of HDL function in the current discussion of HDL and reduction of cardiovascular risk. Hence, in perspective HDL function tests may be a better predictor of cardiovascular risk than HDL-C levels. In project 3 we developed a novel and simple in vivo model to study atherosclerotic plaque regression. By reversal of hyperlipidemia through the inhibition of the microsomal transfer protein we were able to achieve favorable qualitative and quantitative changes in atherosclerotic plaques of LDLr-/- mice within a short-term period. Our results support the current consensus that aggressive LDL-C lowering will promote clinical regression. In conclusion, regression of atherosclerosis can be achieved by various modification of the lipid metabolism. However, further preclinical animal studies and clinical trials are needed to elucidate the exact mechanisms and pathways involved in plaque regression, which represents the ultimate goal in atherosclerosis therapy.
Publications
- HDL and Cardiovascular Risk Time to Call the Plumber? Circulation Research. 2012, 111:1117-20
Hewing B, Moore KJ, Fisher EA
- Preclinical mouse models and methods for the discovery of the causes and treatments of atherosclerosis. Expert Opin Drug Discov. 2012 3:207-16
Hewing B, Fisher EA
(See online at https://doi.org/10.1517/17460441.2012.660143) - Rationale for cholesteryl ester transfer protein inhibition. Curr Opin Lipidol. 2012, 23:372-6
Hewing B, Fisher EA
(See online at https://doi.org/10.1097/MOL.0b013e328353ef1d)
