Novel Mouse Model of Coronary Atherosclerosis With Myocardial Infarction: Insights Into Human CAD

作者：Hong Chen, Qing Wan, Jianfeng Yang, Haojie Rao, Chuansheng Xu, Pengfei Xu, Xuejian Yang, Helen Y.-C. Wang, Wei Feng, Liqing Wang, Magnus Bäck, Robert E. Widdop, Feng Liu, Hong Lü, Alan Daugherty, Shengshou Hu, Garret A. FitzGerald, De‐Pei Liu, Yü Huang, Weijun Jin, Miao Wang · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.125.326409 · 被引用次数：12 · 研究领域：Nitric Oxide and Endothelin Effects、Atherosclerosis and Cardiovascular Diseases、Cardiac Fibrosis and Remodeling

BACKGROUND: Coronary artery disease is a chronic and multifactorial disease with acute manifestations. Little is known about the concomitant impact of hypercholesterolemia and hypertension on the development of coronary atherosclerosis. METHODS: ApoE (apolipoprotein E) and Scarb1 (scavenger receptor class B, type I), both associated with human hypercholesterolemia, were inactivated in mice by inserting a Scarb1 knockdown cassette downstream of the ApoE promoter. Meanwhile, a doxycycline-inducible Ang II (angiotensin II) expression cassette was introduced. The resultant mutant mice ( ApoE SA/SA ), isolated arteries, and pharmacological/genetic interventions were employed to assess the impacts of hypercholesterolemia and hypertension on coronary atherosclerosis and mechanisms. RESULTS: ApoE SA/SA mice developed mild coronary atherosclerosis with heart failure after chronic feeding with western diet. Strikingly, additional Ang II–induced hypertension, but not norepinephrine-induced hypertension, drastically accelerated coronary atherogenesis, exhibiting endothelial erosion, myeloid cell infiltration, spontaneous plaque rupture, and myocardial infarction, which was Ang II type 1 receptor–dependent. In contrast to this severe coronary atherosclerosis, femoral arteries were resistant to atherogenesis. Proteomic profiling revealed substantial differences in vasomotor reactivity and inflammation. Endothelium-dependent dilatation of coronary arteries was highly susceptible to the comb...