Metformin induces cardioprotection against ischaemia/reperfusion injury in the rat heart 24 hours after administration
Metformin induces cardioprotection against ischaemia/reperfusion injury in the rat heart 24 hours after administration
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DOI：
10.1111/j.1742-7843.2008.00234.x
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发表时间：
2008-07-01
影响因子：
3.1
通讯作者：
Lund, Sten
中科院分区：
文献类型：
--
作者：
Solskov, Lasse;Lofgren, Bo;Lund, Sten
英国前瞻性糖尿病研究表明，降血糖药物二甲双胍与一组肥胖2型糖尿病患者的心血管事件减少有关。能量感应酶AMP活化蛋白激酶（AMPK）已被证明在缺血性心脏中发挥重要的保护作用，并被二甲双胍激活。本研究的目的是确定二甲双胍单次给药后24小时是否可保护心肌免受实验诱导的缺血，并进一步确定二甲双胍单次给药是否会导致心肌AMPK活性急性增加。Wistar大鼠单次经口给予二甲双胍（250 mg/kg体重）或单次经口给予生理盐水。24小时后，心脏进行Langendorff灌注，并进行45分钟的冠状动脉闭塞。通过用氯化三苯基四氮唑（TTC）和伊文思蓝染色来确定肿瘤大小，并表示为风险区的百分比（IS/AAR %）。在施用二甲双胍或盐水后2小时测量亚型特异性AMPK活性。与对照组相比，二甲双胍治疗组的颅内压显著降低（I/R：19.9 +/- 3.9% vs 36.7 +/-3.6%，P < 0.01，n = 8-14）。二甲双胍单次口服给药后2小时AMPK-α 2活性增加约2倍（P < 0.015，n = 10）。总之，二甲双胍单次给药导致给药后2小时测量的心肌AMPK活性急性增加，并诱导二甲双胍给药后24小时心肌梗死面积显著减少。AMPK活性增加可能是二甲双胍心脏保护作用机制中的重要信号介质。
The UK Prospective Diabetes Study demonstrated that the hypoglycaemic drug metformin is associated with a reduction in cardiovascular events in a group of obese type 2 diabetes patients. The energy sensing enzyme AMP-activated protein kinase (AMPK) has been indicated to play an important protective role in the ischaemic heart and is activated by metformin. The aim of this study was to determine whether a single dose of metformin protects the myocardium against experimentally induced ischaemia 24 hr after the administration, and furthermore to determine whether a single dose of metformin results in an acute increase in myocardial AMPK activity. Wistar rats were given either a single oral dose of metformin (250 mg/kg body weight), or a single oral dose of saline. After 24 hr, the hearts were Langendorff-perfused and subjected to 45 min. of coronary artery occlusion. Infarct size was determined by staining with triphenyltetrazoliumchloride (TTC) and Evans Blue and expressed as a percentage of the risk zone (IS/AAR %). Isoform specific AMPK activity was measured 2 hr after administration of metformin or saline. Infarct size was significantly reduced in the metformin treated (I/R: 19.9 +/- 3.9% versus 36.7 +/- 3.6%, P < 0.01, n = 8-14) compared to the control group. A single oral dose of metformin resulted in an approximately similar to 2-fold increase in AMPK-alpha 2 activity 2 hr after administration (P < 0.015, n = 10). In conclusion, a single dose of metformin results in an acute increase in myocardial AMPK activity measured 2 hr after administration and induces a significant reduction in myocardial infarct size 24 hr after metformin administration. Increased AMPK activity may be an important signal mediator involved in the mechanisms behind the cardioprotective effects afforded by metformin.