Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice
Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice
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DOI：
10.1152/ajpheart.00465.2014
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发表时间：
2015-05-01
影响因子：
4.8
通讯作者：
Bellien, Jeremy
中科院分区：
文献类型：
--
作者：
Roche, Clothilde;Besnier, Marie;Bellien, Jeremy
这项研究提出了这样的假设：抑制可溶性环氧化物水解酶（sEH）介导的环氧脂肪酸（尤其是环氧二十碳三烯酸）的降解，除了先前证明的对葡萄糖稳态的有益作用之外，还对胰岛素抵抗中的心血管损伤具有额外的影响。将 sEH 抑制剂反式-4-[4-(3-金刚烷-1-基脲基)-环己氧基]-苯甲酸（t-AUCB；饮用水中 10 mg/l）的心血管和代谢作用与磺酰脲类格列本脲（80 mg/l）的心血管和代谢作用进行比较，两者均在接受高脂肪饮食（HFD；60% 脂肪）16 次的 FVB 小鼠中给药 8 周。一周。将食用对照食物（10%脂肪）的小鼠和未治疗的 HFD 小鼠作为对照。格列本脲和 t-AUCB 同样可以预防 HFD 小鼠空腹血糖升高，但只有 t-AUCB 可以改善葡萄糖耐量并减少糖异生，而不会改变体重增加。此外，t-AUCB 可减少脂肪组织炎症、血浆游离脂肪酸和低密度脂蛋白胆固醇，并预防肝脂肪变性。此外，通过离体冠状动脉肌电图评估，只有 sEH 抑制剂能改善内皮依赖性乙酰胆碱松弛。这种改善与环氧二十碳三烯酸和一氧化氮途径的恢复有关，一氧化氮合酶和细胞色素 P-450 环氧化酶抑制剂 L-NA 和 MSPPOH 对这些松弛的抑制作用增强表明了这一点。此外，t-AUCB 可减少心脏肥大、纤维化和炎症，并改善舒张功能，E/A 比值增加（超声心动图）和舒张末期压力-容积关系斜率降低（有创血流动力学）证明了这一点。这些结果表明，sEH 抑制可改善肥胖胰岛素抵抗小鼠的冠状动脉内皮功能并预防心脏重塑和舒张功能障碍。
This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in insulin resistance, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor trans-4-[4-(3-adamantan-1-ylureido)- cyclohexyloxy]-benzoic acid (t-AUCB; 10 mg/l in drinking water) were compared with those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 wk in FVB mice subjected to a high-fat diet (HFD; 60% fat) for 16 wk. Mice on control chow diet (10% fat) and nontreated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice, but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids, and LDL cholesterol and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the nitric oxide synthase and cytochrome P-450 epoxygenase inhibitors L-NA and MSPPOH on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis, and inflammation and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the end-diastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that sEH inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese insulin-resistant mice.