The Effects of Diet on Occlusive Coronary Artery Atherosclerosis and Myocardial Infarction in Scavenger Receptor Class B, Type 1/Low-Density Lipoprotein Receptor Double Knockout Mice
The Effects of Diet on Occlusive Coronary Artery Atherosclerosis and Myocardial Infarction in Scavenger Receptor Class B, Type 1/Low-Density Lipoprotein Receptor Double Knockout Mice
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DOI：
10.1161/atvbaha.114.304200
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发表时间：
2014-11-01
影响因子：
8.7
通讯作者：
Trigatti, Bernardo L.
中科院分区：
文献类型：
--
作者：
Fuller, Mark;Dadoo, Omid;Trigatti, Bernardo L.
目的载脂蛋白E基因敲除小鼠和低形态小鼠高密度脂蛋白受体I型清道夫受体B（SR-BI）缺陷分别导致自发性或饮食诱导性冠状动脉粥样硬化（CA）闭塞、心肌梗死和早期死亡。在这里，我们研究SR-BI缺乏对心血管表型的影响，在低密度脂蛋白受体（LDLR）基因敲除小鼠喂养不同的动脉粥样硬化dietes.Approach和结果SR-BI/LDLR双基因敲除和控制LDLR基因敲除小鼠喂养含有不同量的脂肪，胆固醇和胆酸钠的动脉粥样硬化饮食。与喂食相同饮食的LDLR敲除小鼠相比，喂食高胆固醇致动脉粥样硬化饮食的双敲除小鼠的存活率显著降低。除了增加饮食加速的主动脉窦动脉粥样硬化，我们观察到显着的饮食诱导的CA动脉粥样硬化的双敲除小鼠和饮食依赖性的血小板聚集在CA动脉粥样硬化斑块。在喂食高胆固醇饮食的双基因敲除小鼠中，这伴随着大量的心肌纤维化。与对照LDLR敲除小鼠相比，动脉粥样硬化饮食喂养的双敲除小鼠也表现出更高的循环细胞因子水平，单核细胞增多伴Ly 6C（hi）和Ly 6C（int）单核细胞比例增加，以及CA内皮细胞中更高的粘附分子表达。SR-BI中的富血小板CA疾病/LDLR双基因敲除小鼠受致动脉粥样硬化饮食中胆固醇和胆酸盐含量的影响，并伴随血管细胞表达增加CA中的粘附分子-1和细胞间粘附分子-1，并增加循环中的Ly 6C（hi）和Ly 6C（int）单核细胞。SR-BI缺陷小鼠CA内皮细胞中血管细胞粘附分子-1和细胞间粘附分子-1的增加可能解释了CA中动脉粥样硬化的易感性增加。
Objective 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(int) monocytes in circulation. The increased vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in CA endothelial cells in SR-BI-deficient mice likely explains their increased susceptibility to atherosclerosis in CAs.