The HDL receptor, scavenger receptor class B type I (SR-BI), is expressed on the surface of multiple cell types and has been shown to mediate both HDL-dependent atheroprotective © 2014 American Heart Association, Inc.Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.304200Objective-Deficiency of the high-density lipoprotein receptor, scavenger receptor class B, type I (SR-BI), in apolipoprotein E knockout or hypomorphic mice, respectively, results in spontaneous or diet-inducible occlusive coronary artery (CA) atherosclerosis, myocardial infarction, and early death. Here, we examine effects of SR-BI deficiency on cardiovascular phenotypes in low-density lipoprotein receptor (LDLR) knockout mice fed different atherogenic diets. Approach and Results-SR-BI/LDLR double knockout and control LDLR knockout mice were fed atherogenic diets containing different amounts of fat, cholesterol, and sodium cholate. Double knockout mice fed atherogenic diets high in cholesterol exhibited significantly reduced survival compared with LDLR knockout mice fed the same diets. In addition to increased diet-accelerated aortic sinus atherosclerosis, we observed significant diet-induced CA atherosclerosis in double knockout mice and diet-dependent accumulation of platelets in CA atherosclerotic plaques. This was accompanied by substantial myocardial fibrosis in double knockout mice fed high cholesterol diets. Atherogenic diet fed double knockout mice also exhibited higher circulating cytokine levels, monocytosis with increased proportions of Ly6C hi and Ly6C int monocytes, and higher adhesion molecule expression in CA endothelial cells compared with control LDLR knockout mice. Conclusions-Diet-accelerated atherosclerosis and occlusive, platelet-rich CA disease in SR-BI/LDLR double knockout mice is affected by amounts of cholesterol and cholate in atherogenic diets and is accompanied by increased expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in CAs and increased Ly6C hi and Ly6C Fuller et al Coronary Atherosclerosis in SR-BI/LDLR dKO Mice 2395signaling 8,9 and selective lipid transfer between HDL and cells, which is critical for functional reverse cholesterol transport, the major avenue for cholesterol removal from peripheral tissues.8,10 Deficiency of SR-BI not only accelerates atherosclerosis in the aortic sinus of apoE knockout mice 11 but also renders these mice susceptible to spontaneous occlusive CA atherosclerosis, myocardial infarction, and ultimately early death. 12 A related model, the SR-BI knockout/apoE hypomorphic mouse, develops a similar phenotype when fed high fat, high cholesterol (HFC) diets. 13,14 We have previously shown that SR-BI deficiency increases atherosclerosis in the aortas of LDLR knockout mice fed a high-fat (HF) Western-type diet; however, reduced survival was not observed in these mice, and CA atherosclerosis was not assessed. 15In the current study, we tested the effects of feeding SR-BI/ LDLR double knockout (dKO) mic...

Highlights d Single-cell RNA-seq reveals an altered cell landscape in dystrophic skeletal muscle d Classification of interstitial stem cell states from healthy and dystrophic muscle d Adipo-regulatory cells (Aregs) block adipogenesis through GDF10 secretion d The amount of Aregs decreases in dystrophic muscle, thereby increasing fat depots