Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening
Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening
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DOI：
10.1007/s00395-007-0691-y
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发表时间：
2008-05-01
影响因子：
9.5
通讯作者：
Yellon, Derek M.
中科院分区：
文献类型：
--
作者：
Bhamra, Gurpreet S.;Hausenloy, Derek J.;Yellon, Derek M.
背景在大多数研究中，二甲双胍已被证明对糖尿病患者具有心脏保护作用，但其机制尚不清楚。我们假设二甲双胍通过Akt介导的抑制线粒体通透性转换孔（mPTP）开放来保护缺血心脏。材料与方法正常血糖Wistar大鼠和糖尿病Goto-Kakizaki（GK）大鼠（N ≥ 6/组）离体心脏灌流，缺血35 min，再灌注120 min。在再灌注时单独或与LY 294002（15 μ mol/l）（一种PI 3 K抑制剂）一起加入二甲双胍（50 μ mol/l）15分钟。测量细胞大小和Akt磷酸化。此外，测定了二甲双胍对从两种菌株分离的成年心肌细胞中mPTP开放的影响。结果如下：二甲双胍降低了Wistar（35 +/- 2.7%二甲双胍对62 +/- 3.0%对照：P < 0.05）和GK心脏（43 +/- 4.7%二甲双胍对60 +/- 3.8%对照：P < 0.05）的梗死面积。这种保护伴随着Akt磷酸化的显著增加。LY 294002消除了二甲双胍诱导的Akt磷酸化和二甲双胍在Wistar大鼠中的梗死限制作用（61 +/- 6.7%二甲双胍+LY 294002对比35 +/- 2.7%二甲双胍：P < 0.05）和GK大鼠（56 +/- 5.7%二甲双胍+LY 294002对比43 +/- 4.7%二甲双胍：P < 0.05）。此外，二甲双胍以LY敏感的方式显著抑制了氧化应激的Wistar和GK心肌细胞中的mPTP开放和随后的僵直挛缩。结论我们报告称，再灌注时给予二甲双胍可减少非糖尿病心脏和糖尿病心脏的心肌梗死面积，这种保护作用是通过PI 3 K介导的，并与Akt磷酸化相关。此外，心脏保护似乎通过PI 3 K介导的mPTP开放抑制来执行。这些发现可以部分解释在糖尿病患者的临床研究中观察到的二甲双胍的心脏保护特性。
Background In the majority of studies, metformin has been demonstrated to cardioprotect diabetic patients, the mechanism of which is unclear. We hypothesized that metformin cardioprotects the ischemic heart through the Akt- mediated inhibition of mitochondrial permeability transition pore ( mPTP) opening. Materials and methods Isolated perfused hearts from normoglycemic Wistar or from diabetic Goto-Kakizaki ( GK) rats ( N >= 6/ group) were subjected to 35 min ischemia and 120 min of reperfusion. Metformin ( 50 mu mol/ l) was added for 15 min at reperfusion, alone or with LY294002 ( 15 mu mol/ l), a PI3K inhibitor. Infarct size and Akt phosphorylation were measured. Furthermore, the effect of metformin on mPTP opening in adult cardiomyocytes isolated from both strains was determined. Results: Metformin reduced infarct size in both Wistar ( 35 +/- 2.7% metformin vs. 62 +/- 3.0% control: P < 0.05) and GK hearts ( 43 +/- 4.7% metformin vs. 60 +/- 3.8% control: P < 0.05). This protection was accompanied by a significant increase in Akt phosphorylation. LY294002 abolished the metformin- induced Akt phosphorylation and the infarct- limiting effect of metformin in Wistar ( 61 +/- 6.7% metformin + LY294002 vs. 35 +/- 2.7% metformin: P < 0.05) and GK rats ( 56 +/- 5.7% metformin + LY294002 vs. 43 +/- 4.7% metformin: P < 0.05). In addition, metformin significantly inhibited mPTP opening and subsequent rigor contracture in both Wistar and GK cardiomyocytes subjected to oxidative stress, in a LY- sensitive manner. Conclusions We report that metformin given at the time of reperfusion reduces myocardial infarct size in both the non- diabetic and diabetic heart and this protective effect is mediated through PI3K and is associated with Akt phosphorylation. Furthermore, cardioprotection appears to be executed through a PI3K- mediated inhibition of mPTP opening. These findings may explain in part the cardioprotective properties of metformin observed in clinical studies of diabetic patients.