Ezetimibe Ameliorates Cardiovascular Complications and Hepatic Steatosis in Obese and Type 2 Diabetic db/db Mice
Ezetimibe Ameliorates Cardiovascular Complications and Hepatic Steatosis in Obese and Type 2 Diabetic db/db Mice
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DOI：
10.1124/jpet.110.170373
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发表时间：
2010-10-10
影响因子：
3.5
通讯作者：
Kim-Mitsuyama, Shokei
中科院分区：
文献类型：
--
作者：
Fukuda, Masaya;Nakamura, Taishi;Kim-Mitsuyama, Shokei
2 型糖尿病在心血管疾病的发展中起着重要作用。本研究旨在研究依折麦布（一种有效的胆固醇吸收抑制剂）对肥胖和 2 型糖尿病 db/db 小鼠心血管损伤的影响。饲喂西式饮食的糖尿病 db/db 小鼠接受依折麦布治疗 9 周，并检查其对心血管损伤和肝脂肪变性的影响。依泽替米贝治疗 db/db 小鼠可显着改善血管内皮功能，这与减少的磷酸 Akt 和磷酸内皮一氧化氮合酶 ( eNOS) 的恢复有关。此外，依折麦布还可降低 db/db 小鼠血管超氧化物水平，同时减弱 NADPH 氧化酶亚基 gp91(phox) 和 Nox4 的作用，并防止铜/锌超氧化物歧化酶 (SOD) 和细胞外 SOD 的下调。因此，依折麦布对糖尿病小鼠血管内皮功能的改善似乎归因于eNOS功能的改善和氧化应激的减弱。依折麦布治疗还显着减轻糖尿病小鼠的心脏间质纤维化和冠状动脉增厚，并改善心脏巨噬细胞浸润。心脏损伤的改善也与 NADPH 氧化酶介导的氧化应激的减弱有关。此外，依折麦布显着预防糖尿病小鼠的肝脏脂肪变性、炎症和氧化应激。我们的工作提供了第一个证据，证明依折麦布可以预防糖尿病小鼠的心血管损伤和肝脂肪变性。这些有益效果归因于氧化应激和炎症的减弱以及 eNOS 功能的改善。因此，我们认为依折麦布可能是一种有前景的肥胖和2型糖尿病治疗药物。
Type 2 diabetes plays a major role in the development of cardiovascular diseases. The present study was undertaken to investigate the effect of ezetimibe, a potent cholesterol absorption inhibitor, on cardiovascular injury of obese and type 2 diabetic db/db mice. Diabetic db/db mice fed a Western diet were given ezetimibe for 9 weeks, and the effects on cardiovascular injury and hepatic steatosis were examined. Ezetimibe treatment of db/db mice significantly improved vascular endothelial function, which was associated with the restoration of the decreased phospho-Akt and phospho-endothelial nitric-oxide synthase ( eNOS). Moreover, ezetimibe also reduced vascular superoxide levels in db/db mice, accompanied by the attenuation of NADPH oxidase subunit gp91(phox) and Nox4 and the prevention of down-regulation of Cu/Zn-superoxide dismutase ( SOD) and extracellular SOD. Thus, the improvement of vascular endothelial function by ezetimibe in diabetic mice seems to be attributed to the improvement of eNOS function and the attenuation of oxidative stress. Ezetimibe treatment also significantly attenuated cardiac interstitial fibrosis and coronary arterial thickening of diabetic mice and ameliorated cardiac macrophage infiltration. This improvement of cardiac injury was also related to the attenuation of NADPH oxidase-mediated oxidative stress. Furthermore, ezetimibe significantly prevented hepatic steatosis, inflammation, and oxidative stress in diabetic mice. Our work provides the first evidence that ezetimibe prevented cardiovascular injury and hepatic steatosis in diabetic mice. These beneficial effects were attributed to the attenuation of oxidative stress and inflammation and the improvement of eNOS function. Therefore, we propose that ezetimibe may be a promising therapeutic drug for obese and type 2 diabetes.