Abstract 11508: Macrophage-Specific Disruption of HMG-CoA Reductase Inhibited the Development of Atherosclerosis
Inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in the cholesterol biosynthesis, is the most effective way to lower plasma cholesterol level. Accumulating evidence has suggested that HMGCR inhibitor, statin, inhibits the occurrence of coronary heart diseases via a pathway independent of cholesterol-lowering. Besides anti-inflammation, a wide variety of effects on the arterial wall cells have been proposed to mediate the pleiotropic effects. However, little is known about its effects on monocyte/macrophages, especially in in vivo setting. To address this, we have generated mice lacking HMGCR in macrophage-specific manner (M-HMGCRKO) by crossing mice overexperssing Cre recombinase under the promoter of lysozyme to floxed HMGCR mice (HMGCRfl/fl).
Southern blot analysis showed, 50% of HMGCR gene was disrupted in peritoneal macrophages (p<0.05). mRNA level of HMGCR was reduced to the same degree. Numbers of circulating monocytes were reduced by 45.9% (p<0.001). Adhesiveness of peritoneal macrophages to plastic dish reduced by 32.6% in M-HMGCRKO mice (p<0.05).
To examine the effect of the absence of HMGCR in macrophages on the development of atherosclerosis, we generated mice lacking both macrophage HMGCR and LDL receptor (M-HMGCRKO/LDLRKO). After 12 weeks on atherogenic diet, M-HMGCRKO/LDLRKO mice were leaner by 18.7% (p<0.01) and less hypercholesterolemic by 36.6% (p<0.001) than HMGCRfl/fl/LDLRKO mice. The reduced weight was primarily attributable to reduced food intake (-18.7%, p<0.001). M-HMGCRKO/LDLRKO mice developed less atherosclerotic lesions than M-HMGCRfl/fl/LDLRKO mice (cross-section of aortic root: 8.3±3.7 vs. 22.5±6.4%, p<0.0001, and en face of aorta: 17.3±7.5 vs. 55.7±3.5X105 μm2, p<0.0001). The lesion size showed significant positive correlation with body weight (r=0.63, p=0.015), but not with plasma cholesterol levels.
In conclusion, genetic disruption of HMGCR in macrophages inhibited the development of atherosclerosis in hypercholesterolemic mice even though the disruption was partial. In addition to the changes in the numbers and functions of monocyte/macrophage, the metabolic changes might contribute to the alleviation of the atherosclerotic lesion formation.
- © 2011 by American Heart Association, Inc.