Early Development of Calcific Aortic Valve Disease and Left Ventricular Hypertrophy in a Mouse Model of Combined Dyslipidemia and Type 2 Diabetes Mellitus
Early Development of Calcific Aortic Valve Disease and Left Ventricular Hypertrophy in a Mouse Model of Combined Dyslipidemia and Type 2 Diabetes Mellitus
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DOI：
10.1161/atvbaha.114.304205
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发表时间：
2014-10-01
影响因子：
8.7
通讯作者：
Marette, Andre
中科院分区：
文献类型：
--
作者：
Le Quang, Khai;Bouchareb, Rihab;Marette, Andre
方法和结果-当与非糖尿病LDLr-/-/ApoB（100/100）相比时，糖尿病LDLr-/-/ApoB（100/100）/IGF-II小鼠表现出类似的血脂异常和肥胖，但当喂食高脂肪/蔗糖/胆固醇饮食6个月时发展为2型糖尿病。LDLr-/-/ApoB（100/100）/IGF-II小鼠与C57 BL 6相比显示左心室肥大，但LDLr-/-/ApoB（100/100）小鼠未显示。经胸超声心动图显示，与LDLr-/-/ApoB（100/100）相比，喂食高脂肪/蔗糖/胆固醇的LDLr-/-/ApoB（100/100）/IGF-II小鼠的左心室收缩缩短分数和舒张功能均显著降低。重要的是，我们发现高脂/蔗糖/胆固醇饮食的LDLr-/-/ApoB（100/100）/IGF-II小鼠与LDLr-/-/ApoB（100/100）动物相比，主动脉瓣峰值喷射速度显著增加。显微断层扫描和茜素红染色表明主动脉瓣钙化，而电子显微镜和能量色散X射线光谱进一步揭示了主动脉瓣叶的矿化和糖尿病小鼠中存在炎性浸润。研究表明，上调心肌组织中的肥大基因（anp，bnp，b-mhc）和成骨基因（spp 1，bglap，runx 2）在主动脉tissues. Conclusions的，我们已经建立了糖尿病倾向的LDLr-/-/ApoB（100/100）/IGF-Ⅱ小鼠作为一种新的模型钙化主动脉瓣疾病。我们的研究结果与越来越多的临床证据一致，即2型糖尿病的代谢异常状态有助于主动脉瓣的早期矿化和钙化主动脉瓣疾病的发病机制。
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.