Nicorandil alleviates apoptosis in diabetic cardiomyopathy through PI3K/Akt pathway
Nicorandil alleviates apoptosis in diabetic cardiomyopathy through PI3K/Akt pathway
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尼可地尔通过 PI3K/Akt 通路减轻糖尿病心肌病细胞凋亡
DOI：
10.1111/jcmm.14413
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发表时间：
2019-08-01
影响因子：
5.3
通讯作者：
An, Fengshuang
中科院分区：
文献类型：
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作者：
Wang, Xuyang;Pan, Jinyu;An, Fengshuang
尼可地尔通过其抗缺氧和抗氧化作用发挥心肌保护作用。在这里，我们研究了它是否在糖尿病性心肌病中起抗凋亡作用。Sprague-Dawley大鼠饲喂高脂肪饲料；然后单次腹腔注射链脲佐菌素。选择空腹血糖（FBG）高于11.1 mmol/L的大鼠作为模型。造模8周后，大鼠给予尼可地尔（7.5 mg/kg d、15 mg/kg d）治疗4周。用尼可地尔处理H9c2心肌细胞，然后用高糖（33.3 mmol/L）刺激。TUNEL检测bcl-2、bax、caspase-3水平。5-HD对尼可地尔有抑制作用。此外，使用PI3K抑制剂（米替福辛）和mTOR抑制剂（雷帕霉素）抑制PI3K/Akt通路。结果显示，与未治疗组相比，nicorandil （7.5 mg/kg day和15mg/kg day）可提高糖尿病大鼠血清NO水平和心脏eNOS水平。尼可地尔还能改善、缓解心功能障碍，降低细胞凋亡水平。在体外实验中，与未给药组相比，尼可地尔（100 μ mol）可显著降低高糖诱导的H9C2心肌细胞凋亡水平。尼可地尔对细胞凋亡的影响被5-HD阻断，并伴有PI3K、Akt、eNOS和mTOR磷酸化的抑制。在抑制PI3K/Akt通路后，尼可地尔的保护作用受到抑制。这些结果证实，作为NO供体，尼可地尔还可以抑制PI3K/Akt通路介导的糖尿病心肌病细胞凋亡。
Nicorandil exerts myocardial protection through its antihypoxia and antioxidant effects. Here, we investigated whether it plays an anti-apoptotic role in diabetic cardiomyopathy. Sprague-Dawley rats were fed with high-fat diet; then single intraperitoneal injection of streptozotocin was performed. Rats with fasting blood glucose (FBG) higher than 11.1 mmol/L were selected as models. Eight weeks after the models were built, rats were treated with nicorandil (7.5 mg/kg day and 15 mg/kg day respectively) for 4 weeks. H9c2 cardiomyocytes were treated with nicorandil and then stimulated with high glucose (33.3 mmol/L). TUNEL assay and level of bcl-2, bax and caspase-3 were measured. 5-HD was used to inhibit nicorandil. Also, PI3K inhibitor (Miltefosine) and mTOR inhibitor (rapamycin) were used to inhibit PI3K/Akt pathway. The results revealed that nicorandil (both 7.5 mg/kg day and 15mg/kg day) treatment can increase the level of NO in the serum and eNOS in the heart of diabetic rats compared with the untreated diabetic group. Nicorandil can also improve relieve cardiac dysfunction and reduce the level of apoptosis. In vitro experiments, nicorandil (100 mu mol) can attenuate the level of apoptosis stimulated by high glucose significantly in H9C2 cardiomyocyte compared with the untreated group. The effect of nicorandil on apoptosis was blocked by 5-HD, and it was accompanied with inhibition of the phosphorylation of PI3K, Akt, eNOS, and mTOR. After inhibition of PI3K/Akt pathway, the protective effect of nicorandil is restrained. These results verified that as a NO donor, nicorandil can also inhibit apoptosis in diabetic cardiomyopathy which is mediated by PI3K/Akt pathway.