Cardiac-Specific Overexpression of CYP2J2 Attenuates Diabetic Cardiomyopathy in Male Streptozotocin-Induced Diabetic Mice
Cardiac-Specific Overexpression of CYP2J2 Attenuates Diabetic Cardiomyopathy in Male Streptozotocin-Induced Diabetic Mice
复制标题
CYP2J2 心脏特异性过度表达可减轻链脲佐菌素诱导的雄性糖尿病小鼠的糖尿病心肌病
DOI：
10.1210/en.2012-2166
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发表时间：
2013-08-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Dao Wen
中科院分区：
文献类型：
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作者：
Ma, Ben;Xiong, Xiaojv;Wang, Dao Wen
细胞色素P450（CYP 1A 1）环氧合酶将花生四烯酸代谢为具有生物活性的顺式-环氧二十碳三烯酸，其具有有效的血管舒张、血管扩张、抗凋亡和抗糖尿病特性。在这里，我们展示了心脏特异性过表达的CYP 2 J2对高脂饮食喂养的低剂量链脲佐菌素治疗小鼠的糖尿病心肌病和胰岛素抵抗的影响。在心脏特异性CYP 2 J2转基因小鼠中通过HF和链脲佐菌素诱导糖尿病心肌病。使用ELISA试剂盒监测生理参数和全身代谢参数。腹腔注射葡萄糖耐量试验和高胰岛素-正葡萄糖钳夹试验提示胰岛素抵抗。采用超声心动图和Millar导管系统评价心功能。实时荧光定量PCR和Western blotting检测信号通路。α MHC-CYP 2 J2转基因小鼠显示出显著降低的血浆葡萄糖和胰岛素水平、改善的葡萄糖耐量和增加的心脏葡萄糖摄取。此外，α-MHC-CYP 2 J2转基因小鼠显著保护HF-链脲佐菌素诱导的糖尿病心肌病。引人注目的是，CYP 2 J2过表达减弱了糖尿病诱导的心肌肥大。我们的结论是，心脏特异性过表达的CYP 2 J2显着防止糖尿病性心肌病，这可能是由于改善心脏胰岛素抵抗，葡萄糖摄取和逆转心脏肥大。相关机制可能包括过氧化物酶体增殖物激活受体γ的上调、胰岛素受体和AMP激活的蛋白激酶信号通路的激活以及通过增强心房利钠肽产生抑制活化T细胞核因子c3信号。这些结果表明，CYP 2 J2环氧合酶代谢产物可能在血浆葡萄糖稳态中起重要作用，增强环氧二十碳三烯酸活化可能作为预防糖尿病心肌病的有效治疗策略。
Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active cis-epoxyeicosatrienoic acids, which have potent vasodilatory, antiinflammatory, antiapoptotic, and antidiabetes properties. Here, we showed the effects of cardiac-specific overexpression of CYP epoxygenase 2J2 (CYP2J2) on diabetic cardiomyopathy and insulin resistance in high-fat (HF) diet fed, low-dose streptozotocin-treated mice. Diabetic cardiomyopathy was induced by HF and streptozotocin in cardiac-specific CYP2J2 transgenic mice. Physiological parameters and systemic metabolic parameters were monitored using ELISA kits. Intraperitoneal injection glucose tolerance test and hyperinsulinemic-euglycemic clamp study were implied to indicate insulin resistance. Cardiac function was assessed by echocardiography and Millar catheter system. Real-time PCR and Western blotting were used in signal pathway detection. alpha MHC-CYP2J2 transgenic mice showed significantly lower plasma glucose and insulin levels, improved glucose tolerance, and increased cardiac glucose uptake. Furthermore, alpha MHC-CYP2J2 transgenic mice were significantly protected from HF-streptozotocin-induced diabetic cardiomyopathy. Strikingly, CYP2J2 overexpression attenuated myocardial hypertrophy induced by diabetes. We conclude that cardiac-specific overexpression of CYP2J2 significantly protects against diabetic cardiomyopathy, which may be due to improved cardiac insulin resistance, glucose uptake, and reversal of cardiac hypertrophy. Relevant mechanisms may include up-regulation of peroxisome proliferator-activated receptor gamma, activation of insulin receptor and AMP-activated protein kinase signaling pathways, and inhibition of nuclear factor of activated T cells c3 signal by enhanced atrial natriuretic peptide production. These results suggest that CYP2J2 epoxygenase metabolites likely play an important role in plasma glucose homeostasis, and enhancement of epoxyeicosatrienoic acids activation may serve as an effective therapeutic strategy to prevent diabetic cardiomyopathy.