Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K-Akt signaling in diabetic rats
Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K-Akt signaling in diabetic rats
复制标题
小檗碱通过激活 AMPK 和 PI3K-Akt 信号传导减少糖尿病大鼠的缺血/再灌注诱导的心肌细胞凋亡
DOI：
10.1007/s10495-014-0977-0
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发表时间：
2014-06-01
期刊：
影响因子：
7.2
通讯作者：
Gao, Feng
中科院分区：
文献类型：
--
作者：
Chen, Keke;Li, Guohua;Gao, Feng
糖尿病会增加患心血管疾病的风险。小檗碱（BBR）是一种异喹啉类生物碱，具有降血糖、调节脂代谢等作用。据报道，BBR可降低慢性充血性心力衰竭患者的死亡率。然而，这些有益作用的分子机制尚未完全了解。在本研究中，我们试图确定是否BBR对糖尿病大鼠的心脏缺血/再灌注（I/R）损伤的保护作用及其机制。给雄性Sprague-Dawley大鼠注射低剂量链脲佐菌素并喂食高脂饮食12周以诱导糖尿病。从第9周至第12周开始，对糖尿病大鼠灌胃给予生理盐水或BBR（100、200和400 mg/kg/d）。第12周末，所有大鼠均行心肌缺血30 min，再灌注3 h。BBR可明显改善糖尿病大鼠心肌I/R后心脏舒缩功能的恢复，减少心肌细胞凋亡。此外，在培养的新生大鼠心肌细胞中，BBR（50 μ mol/L）减少缺氧/复氧诱导的心肌细胞凋亡，增加Bcl-2/Bax比值和减少caspase-3的表达，同时增强PI 3 K-Akt的激活和增加腺苷一磷酸活化蛋白激酶（AMPK）和eNOS磷酸化。用PI 3 K/Akt抑制剂wortmannin或AMPK抑制剂化合物C预处理减弱了BBR的抗凋亡作用。我们的研究结果表明，BBR通过激活AMPK和PI 3 K-Akt-eNOS信号通路发挥抗糖尿病大鼠心肌I/R后细胞凋亡和改善心功能的作用。
Diabetes increases the risk of cardiovascular diseases. Berberine (BBR), an isoquinoline alkaloid used in Chinese medicine, exerts anti-diabetic effect by lowering blood glucose and regulating lipid metabolism. It has been reported that BBR decreases mortality in patients with chronic congestive heart failure. However, the molecular mechanisms of these beneficial effects are incompletely understood. In the present study, we sought to determine whether BBR exerts cardioprotective effect against ischemia/reperfusion (I/R) injury in diabetic rats and the underlying mechanisms. Male Sprague-Dawley rats were injected with low dose streptozotocin and fed with a high-fat diet for 12 weeks to induce diabetes. The diabetic rats were intragastrically administered with saline or BBR (100, 200 and 400 mg/kg/d) starting from week 9 to 12. At the end of week 12, all rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion. BBR significantly improved the recovery of cardiac systolic/diastolic function and reduced myocardial apoptosis in diabetic rats subjected to myocardial I/R. Furthermore, in cultured neonatal rat cardiomyocytes, BBR (50 mu mol/L) reduced hypoxia/reoxygenation-induced myocardial apoptosis, increased Bcl-2/Bax ratio and decreased caspase-3 expression, together with enhanced activation of PI3K-Akt and increased adenosine monophosphate-activated protein kinase (AMPK) and eNOS phosphorylation. Pretreatment with either PI3K/Akt inhibitor wortmannin or AMPK inhibitor Compound C blunted the anti-apoptotic effect of BBR. Our findings demonstrate that BBR exerts anti-apoptotic effect and improves cardiac functional recovery following myocardial I/R via activating AMPK and PI3K-Akt-eNOS signaling in diabetic rats.