Abstract 17793: MicroRNA-33 Deficiency Reduced Atherosclerosis Formation In Vivo
Backgrounds; Atherosclerosis is the major cause of vascular disease, such as myocardial infarction, cerebral infarction and peripheral artery disease. Despite vigorous investigations, cardiovascular disease remains the major cause of mortality, worldwide. Therefore, new approaches in preventing and treating atherosclerosis are expected. Recently, we and other researchers reported that microRNA-33 reduced serum HDL-C by targeting ABCA1. Because HDL-C is inversely correlated with cardiovascular disease, we hypothesized that microRNA-33 might affect atherosclerosis formation.
Methods and results; We generated microRNA-33 deficient mice, which showed significant increase of ABCA1 expression in the liver and serum HDL-C. To investigate the function of microRNA-33 on atherosclerosis formation, microRNA-33 and apoE double knockout mice were obtained by mating microRNA-33 deficient mice with apoE deficient mice. Peritoneal macrophages from these double knockout mice showed significant increase of ABCA1 and ABCG1 expression compared to macrophages from apoE deficient mice. In accordance with the increased expression of ABCA1 and ABCG1, cholesterol efflux to both apoA-I and HDL-C were also significantly elevated in peritoneal macrophages from double knockout mice. These mice were fed a western diet containing 0.15% cholesterol for 16 weeks from 6 weeks old and the severity of atherosclerosis was compared. MicroRNA-33 and apoE double knockout mice showed 24% increase in serum HDL-C compared to apoE deficient mice. ApoB-depleted serum from double knockout mice significantly promoted cholesterol efflux in J774 mouse macrophages. Plaque areas and CD68-positive areas at the aortic roots were significantly reduced in double knockout mice compared to apoE deficient mice. (Plaque area; 28.9±1.8% vs. 23.4±1.0% CD-68 positive area 24.9±1.0% vs. 20.5±0.7%)
Conclusions; MicroRNA-33 deficiency reduced atherosclerosis in apoE deficient mice, probably by increasing serum HDL-C, elevating macrophage cholesterol efflux and reducing macrophage content at the plaque. Inhibition of microRNA-33 can be a novel therapeutical approach for atherosclerosis.
- © 2012 by American Heart Association, Inc.