Increased Calcific Aortic Valve Disease in response to a diabetogenic, procalcific diet in the LDLr(-/-)ApoB(100/100) mouse model.
Increased Calcific Aortic Valve Disease in response to a diabetogenic, procalcific diet in the LDLr(-/-)ApoB(100/100) mouse model.
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DOI：
10.1016/j.carpath.2018.02.002
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Giachelli CM
中科院分区：
文献类型：
--
作者：
Scatena M;Jackson MF;Speer MY;Leaf EM;Wallingford MC;Giachelli CM
钙化性主动脉瓣疾病（CAVD）是主动脉瓣狭窄（AS）和心功能不全的主要原因。II型糖尿病（T2 DM）患者发生CAVD的风险较高，其瓣膜的钙化程度高于非糖尿病瓣膜。目前还没有预防或治疗CAVD的药物，而且也非常缺乏可能有助于确定治疗靶点的动物模型。为了开发一种模拟T2 DM患者CAVD结构和功能特征的动物模型，我们在LDLr−/− ApoB 100/100小鼠模型中检测了致糖尿病、前钙饮食及其对CAVD和AS发生率和严重程度的影响。与正常饲料喂养的LDLr −/− ApoB 100/100小鼠相比，喂食定制的致糖尿病、高钙饮食（DB饮食）的LDLr −/− ApoB 100/100小鼠出现高血糖症、高脂血症、动脉粥样硬化增加和肥胖，表明发生了T2 DM和代谢综合征。经胸超声心动图显示，喂食DB饲料的LDLr−/− ApoB 100/100小鼠的血流动力学显著性AS发生率为77%，并出现主动脉瓣叶增厚以及瓣叶和铰链区钙化。相比之下，正常饲料（NC）喂养的LDLr−/− ApoB 100/100小鼠的AS发生率为38%，瓣叶较薄，瓣膜和铰链钙化极少。此外，DB饮食喂养的AS小鼠显示出显著受损的心脏功能，如通过降低的射血分数和缩短分数所确定的。体外矿化实验表明，培养基中葡萄糖浓度升高可促进瓣膜间质细胞（维克）基质钙沉积。通过控制饮食，我们开发了一种新的T2 DM CAVD模型，即高脂血症LDLr−/− ApoB 100/100，该模型显示出与T2 DM和动脉粥样硬化（包括AS）患者中发现的CAVD相似的几个重要功能和结构特征，心功能不全，以及发炎和钙化增厚的瓣尖。重要的是，这种糖尿病模型的高AS发病率可能有助于旨在开发CAVD新治疗方法的机制和转化研究。
Calcific aortic valve disease (CAVD) is a major cause of aortic stenosis (AS) and cardiac insufficiency. Patients with type II diabetes mellitus (T2DM) are at heightened risk for CAVD, and their valves have greater calcification than nondiabetic valves. No drugs to prevent or treat CAVD exist, and animal models that might help identify therapeutic targets are sorely lacking. To develop an animal model mimicking the structural and functional features of CAVD in people with T2DM, we tested a diabetogenic, procalcific diet and its effect on the incidence and severity of CAVD and AS in the, LDLr−/−ApoB100/100 mouse model. LDLr−/−ApoB100/100 mice fed a customized diabetogenic, procalcific diet (DB diet) developed hyperglycemia, hyperlipidemia, increased atherosclerosis, and obesity when compared with normal chow fed LDLr−/−ApoB100/100 mice, indicating the development of T2DM and metabolic syndrome. Transthoracic echocardiography revealed that LDLr−/−ApoB100/100 mice fed the DB diet had 77% incidence of hemodynamically significant AS, and developed thickened aortic valve leaflets and calcification in both valve leaflets and hinge regions. In comparison, normal chow (NC) fed LDLr−/−ApoB100/100 mice had 38% incidence of AS, thinner valve leaflets and very little valve and hinge calcification. Further, the DB diet fed mice with AS showed significantly impaired cardiac function as determined by reduced ejection fraction and fractional shortening. In vitro mineralization experiments demonstrated that elevated glucose in culture medium enhanced valve interstitial cell (VIC) matrix calcium deposition. By manipulating the diet we developed a new model of CAVD in T2DM, hyperlipidemic LDLr−/−ApoB100/100 that shows several important functional, and structural features similar to CAVD found in people with T2DM and atherosclerosis including AS, cardiac dysfunction, and inflamed and calcified thickened valve cusps. Importantly, the high AS incidence of this diabetic model may be useful for mechanistic and translational studies aimed at development of novel treatments for CAVD.
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影响因子：
39.3
作者：
Iung, B;Baron, G;Vahanian, A
通讯作者：
Vahanian, A
DOI：
10.1161/atvbaha.110.211029
发表时间：
2010-12
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Miller JD;Weiss RM;Serrano KM;Castaneda LE;Brooks RM;Zimmerman K;Heistad DD
通讯作者：
Heistad DD
影响因子：
6.1
作者：
Chen, Neal X.;Duan, Danxia;Moe, Sharon M.
通讯作者：
Moe, Sharon M.
DOI：
10.1161/atvbaha.114.304205
发表时间：
2014-10-01
影响因子：
8.7
作者：
Le Quang, Khai;Bouchareb, Rihab;Marette, Andre
通讯作者：
Marette, Andre
影响因子：
3.1
作者：
Liu, Yiwen;Shanahan, Catherine M.
通讯作者：
Shanahan, Catherine M.