| Summary: | 碩士 === 國立清華大學 === 生物醫學工程研究所 === 104 === Atherosclerosis starts with endothelial cells dysfunction. Various adhesion molecules recruit monocytes migrate into the vessel wall and differentiate into macrophages. Subsequently, macrophages uptake oxLDL and drive inflammatory response in atherosclerotic plaques. MicroRNAs (miRs) control the function of endothelial cells, smooth muscle cells and macrophage by targeting mRNA degradation or translation. Recent years, the roles of miRs in inflammatory response during atherosclerosis have been discovered. MiR-146a has been demonstrated to reduce the cholesterol levels, and oxidized low density lipoprotein-induced inflammatory response in macrophage. MiR-146a may have different functions in vascular cells by targeting mRNA to reduce the progression of atherosclerotic. In the present study, we assessed the impact of the genetic loss of miR-146a in a mouse model of atherosclerosis and elucidated the mechanism of miR-146a in regulation of atherosclerosis. We studied the mechanism of miR-146a in ApoE-/- mice which is an experimental model of atherosclerosis. In comparison with miR-146a+/+ ApoE-/- mice fed with high cholesterol diet for 10 weeks , miR-146a-/- ApoE-/- mice showed an increase number and area of atherosclerotic plaque, lipid content and abundant macrophages accumulated in the plaque. In addition, miR-146a-/- ApoE-/- mice also showed an increase in circulating triglyceride and decrease in HDL levels compared with miR-146a+/+ ApoE-/- mice. To elucidate the roles of miR-146a in macrophages, bone marrow derived-macrophages were isolated from miR-146a-/- ApoE-/- and miR-146a+/+ ApoE-/- mice. In comparison with macrophage of miR-146a+/+ ApoE-/-, macrophages of miR-146a-/- ApoE-/- showed a significant oxidized LDL uptake and reduction in cholesterol efflux capacity The expression of cholesterol transporters, including the ATP-binding cassette sub-family A1 (ABCA1) and sub-family G1 (ABCG1) were decreased in miR-146a-/- ApoE-/- macrophages. We demonstrated that toll like receptor 4 (TLR4) is directly targeted by miR-146a. Increase and activation of TLR4 by LPS blocked the liver X receptors target ABCA1 and ABCG1 expression. Overexpression of miR-146a and silence of TLR4 increased the cholesterol efflux capacity and reduced the oxidized LDL uptake. These data demonstrated that TLR4 is involved in miR-146a-mediated regulation of ABCA1 and ABCG1 expression, and miR-146a reduces the progression of atherosclerotic plaque by increasing ABCA1 and ABCG1 protein.
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