Lin Yi-Wei, Liu Pu-Ste, Adhikari Neeta, Hall Jennifer L, Wei Li-Na
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA.
Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA.
J Mol Cell Cardiol. 2015 Feb;79:287-94. doi: 10.1016/j.yjmcc.2014.12.009. Epub 2014 Dec 18.
Atherosclerosis, a syndrome with abnormal arterial walls, is one of the major causes that lead to the development of various cardiovascular diseases. The key initiator of atherosclerosis is cholesterol accumulation. The uncontrolled cholesterol deposition, mainly involving low-density lipoprotein (LDL), causes atheroma plaque formation, which initiates chronic inflammation due to the recruitment of inflammatory cells such as macrophages. Macrophages scavenge excess peripheral cholesterol and transport intracellular cholesterol to high-density lipoprotein (HDL) for excretion or storage. Cholesterol-laden macrophage-derived foam cell formation is the main cause of atherogenesis. It is critical to understand the regulatory mechanism of cholesterol homeostasis in the macrophage in order to prevent foam cells formation and further develop novel therapeutic strategies against atherosclerosis. Here we identified a protein, RIP140 (receptor interacting protein 140), which enhances macrophage-derived foam cell formation by reducing expression of reverse cholesterol transport genes, A TP-binding membrane cassette transporter A-1 (ABCA1) and ATP-binding membrane cassette transporter G-1 (ABCG1). In animal models, we found that reducing RIP140 levels by crossing macrophage-specific RIP140 knockdown (MϕRIP140KD) mice with ApoE null mice effectively ameliorates high-cholesterol diet-induced atherosclerosis. Our data suggest that reducing RIP140 levels in macrophages significantly inhibits atherosclerosis, along with markers of inflammation and the number of macrophages in a western diet fed ApoE null mouse. This study provides a proof-of-concept for RIP140 as a risk biomarker of, and a therapeutic target for, atherosclerosis.
动脉粥样硬化是一种动脉壁异常的综合征，是导致各种心血管疾病发生的主要原因之一。动脉粥样硬化的关键起始因素是胆固醇积累。不受控制的胆固醇沉积，主要涉及低密度脂蛋白（LDL），会导致动脉粥样斑块形成，由于巨噬细胞等炎症细胞的募集引发慢性炎症。巨噬细胞清除外周多余的胆固醇，并将细胞内胆固醇转运至高密度脂蛋白（HDL）进行排泄或储存。富含胆固醇的巨噬细胞源性泡沫细胞形成是动脉粥样硬化发生的主要原因。了解巨噬细胞中胆固醇稳态的调节机制对于预防泡沫细胞形成以及进一步开发抗动脉粥样硬化的新型治疗策略至关重要。在此，我们鉴定出一种蛋白质，RIP140（受体相互作用蛋白140），它通过降低逆向胆固醇转运基因——ATP结合膜盒转运体A-1（ABCA1）和ATP结合膜盒转运体G-1（ABCG1）的表达来增强巨噬细胞源性泡沫细胞的形成。在动物模型中，我们发现通过将巨噬细胞特异性RIP140基因敲低（MϕRIP140KD）小鼠与载脂蛋白E基因敲除小鼠杂交来降低RIP140水平，可有效改善高胆固醇饮食诱导的动脉粥样硬化。我们的数据表明，在喂食西方饮食的载脂蛋白E基因敲除小鼠中，降低巨噬细胞中的RIP140水平可显著抑制动脉粥样硬化，同时降低炎症标志物和巨噬细胞数量。本研究为RIP140作为动脉粥样硬化的风险生物标志物和治疗靶点提供了概念验证。
