Le Quang Khai, Bouchareb Rihab, Lachance Dominic, Laplante Marc-André, El Husseini Diala, Boulanger Marie-Chloé, Fournier Dominique, Fang Xiang Ping, Avramoglu Rita Kohen, Pibarot Philippe, Deshaies Yves, Sweeney Gary, Mathieu Patrick, Marette André
From the Heart and Lung Institute, Laval University, Sainte-Foy, Québec, Canada (K.L.Q., R.B., D.L., M.-A.L., D.E.H., M.-C.B., D.F., X.P.F., R.K.A., P.P., Y.D., P.M., A.M.); and Department of Biology, York University, Toronto, Ontario, Canada (X.P.F., G.S.).
Arterioscler Thromb Vasc Biol. 2014 Oct;34(10):2283-91. doi: 10.1161/ATVBAHA.114.304205. Epub 2014 Aug 14.
OBJECTIVE: This study aimed to determine the potential impact of type 2 diabetes mellitus on left ventricular dysfunction and the development of calcified aortic valve disease using a dyslipidemic mouse model prone to developing type 2 diabetes mellitus. APPROACH AND RESULTS: When compared with nondiabetic LDLr(-/-)/ApoB(100/100), diabetic LDLr(-/-)/ApoB(100/100)/IGF-II mice exhibited similar dyslipidemia and obesity but developed type 2 diabetes mellitus when fed a high-fat/sucrose/cholesterol diet for 6 months. LDLr(-/-)/ApoB(100/100)/IGF-II mice showed left ventricular hypertrophy versus C57BL6 but not LDLr(-/-)/ApoB(100/100) mice. Transthoracic echocardiography revealed significant reductions in both left ventricular systolic fractional shortening and diastolic function in high-fat/sucrose/cholesterol fed LDLr(-/-)/ApoB(100/100)/IGF-II mice when compared with LDLr(-/-)/ApoB(100/100). Importantly, we found that peak aortic jet velocity was significantly increased in LDLr(-/-)/ApoB(100/100)/IGF-II mice versus LDLr(-/-)/ApoB(100/100) animals on the high-fat/sucrose/cholesterol diet. Microtomography scans and Alizarin red staining indicated calcification in the aortic valves, whereas electron microscopy and energy dispersive x-ray spectroscopy further revealed mineralization of the aortic leaflets and the presence of inflammatory infiltrates in diabetic mice. Studies showed upregulation of hypertrophic genes (anp, bnp, b-mhc) in myocardial tissues and of osteogenic genes (spp1, bglap, runx2) in aortic tissues of diabetic mice. CONCLUSIONS: We have established the diabetes mellitus -prone LDLr(-/-)/ApoB(100/100)/IGF-II mouse as a new model of calcified aortic valve disease. Our results are consistent with the growing body of clinical evidence that the dysmetabolic state of type 2 diabetes mellitus contributes to early mineralization of the aortic valve and calcified aortic valve disease pathogenesis.
目的：本研究旨在利用易患2型糖尿病的血脂异常小鼠模型，确定2型糖尿病对左心室功能障碍和钙化性主动脉瓣疾病发展的潜在影响。 方法与结果：与非糖尿病LDLr(-/-)/ApoB(100/100)小鼠相比，糖尿病LDLr(-/-)/ApoB(100/100)/IGF-II小鼠表现出相似的血脂异常和肥胖，但在喂食高脂/高糖/高胆固醇饮食6个月后患上了2型糖尿病。与C57BL6小鼠相比，LDLr(-/-)/ApoB(100/100)/IGF-II小鼠出现左心室肥厚，但LDLr(-/-)/ApoB(100/100)小鼠未出现。经胸超声心动图显示，与LDLr(-/-)/ApoB(100/100)小鼠相比，喂食高脂/高糖/高胆固醇饮食的LDLr(-/-)/ApoB(100/100)/IGF-II小鼠的左心室收缩期分数缩短率和舒张功能均显著降低。重要的是，我们发现，与喂食高脂/高糖/高胆固醇饮食的LDLr(-/-)/ApoB(100/100)动物相比，LDLr(-/-)/ApoB(100/100)/IGF-II小鼠的主动脉峰值射流速度显著增加。显微断层扫描和茜素红染色显示主动脉瓣钙化，而电子显微镜和能量色散X射线光谱进一步揭示糖尿病小鼠主动脉瓣叶的矿化以及炎症浸润的存在。研究表明，糖尿病小鼠心肌组织中肥厚基因（anp、bnp、b-mhc）和主动脉组织中成骨基因（spp1、bglap、runx2）上调。 结论：我们已将易患糖尿病的LDLr(-/-)/ApoB(100/100)/IGF-II小鼠确立为钙化性主动脉瓣疾病的新模型。我们的结果与越来越多的临床证据一致，即2型糖尿病的代谢紊乱状态有助于主动脉瓣的早期矿化和钙化性主动脉瓣疾病的发病机制。
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