Abstract 14595: MicroRNA 33 Deficiency in Leukocytes Reduced the Lipid Accumulation in Atherosclerotic Plaque in ApoE Knockout Mice

Abstract

Although lowering LDL cholesterol with statin is epoch-making treatment for preventing and reducing atherosclerosis, HDL cholesterol raising therapy is still not established. Recently, we and other groups reported that microRNA-33 reduced serum HDL cholesterol by targeting ATP-binding cassette transporter A1 (ABCA1). In fact, microRNA-33 deficient mouse which we generated showed increase in serum HDL cholesterol compared to control. In addition, it is also known that macrophages have an important role in atherosclerosis formation.

Purpose: We assessed the effect of microRNA-33 in macrophages on atherosclerosis formation using bone marrow transplantation (BMT) model.

Methods and Results: Peritoneal macrophages obtained from microRNA-33 and apoE double knockout mice showed significant increase of ABCA1 and ABCG1 expression compared to those from apoE knockout mice. Cholesterol efflux to both apoA-I and HDL cholesterol was also significantly increased in peritoneal macrophages from double knockout mice. To assess the effect of microRNA-33 in macrophages on atherosclerosis formation, we generated apoE knockout mice that were selectively deficient in leukocyte miR-33 using BMT. BMT was performed at the age of 8 weeks old. These mice were fed a western diet for 12 weeks from 12 weeks old, and then severity of atherosclerosis was assessed. Serum HDL-C levels of microRNA-33 and apoE double knockout BM recipients were the same as only apoE knockout BM recipients at the age of 24 weeks old. There was a tendency for a reduction in atherosclerotic plaque formation in microRNA-33 and apoE double knockout BM recipients compared with only apoE knockout BM recipients (p=0.15; 27.1±0.7 vs. 26.6±2.6%), which was not statistically significant. On the other hand, quantification of lipid accumulation by oil red O staining showed a significant decrease in microRNA-33 and apoE double knockout BM recipients compared with apoE BM recipients (p=0.014; 3.2±0.4 vs. 1.9±0.3%).

Conclusions: MicroRNA-33 deficiency in leukocytes reduced lipid accumulation in atherosclerotic plaque, but only had a tendency for a reduction in atherosclerotic plaque formation.