Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms
Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms
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DOI：
10.1152/ajpheart.00873.2007
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发表时间：
2008-06-01
影响因子：
4.8
通讯作者：
Allard, Michael F.
中科院分区：
文献类型：
--
作者：
Saeedi, Ramesh;Parsons, Hannah L.;Allard, Michael F.
据报道，抗糖尿病药物二甲双胍的代谢作用是通过激活心脏和其他组织中amp活化的蛋白激酶（AMPK）而发生的，无论细胞能量状态是否发生变化。在本研究中，我们验证了二甲双胍对心肌代谢具有ampk独立作用的假设。在没有或存在二甲双胍（2 mM）的情况下，对氟烷麻醉的雄性sd大鼠离体工作心脏和培养的心脏源性H9c2细胞的脂肪酸氧化和葡萄糖利用（糖酵解和葡萄糖摄取）进行了测量。二甲双胍显著改变心脏和H9c2细胞的脂肪酸氧化和葡萄糖利用。在两种模型系统中，二甲双胍都没有明显改变AMPK活性，在完整的心脏中也没有观察到能量状态的损害。此外，6-[4-（2-哌啶-1-乙基氧基）苯基]-3-吡啶-4-酰基-吡唑罗[1,5-a]嘧啶（化合物C）对AMPK的抑制作用，一种公认的AMPK药理抑制剂，或AMPK的显性阴性形式的过度表达，都未能阻止二甲双胍在H9c2细胞中的代谢作用。H9c2细胞暴露于p38丝裂原活化蛋白激酶（p38 MAPK）或蛋白激酶C （PKC）抑制剂中，分别部分或完全消除了二甲双胍诱导的这些细胞代谢改变。因此二甲双胍在心肌中的代谢作用可以独立于AMPK活性的变化而发生，并可能由p38 MAPK-和pkc依赖机制介导。
The metabolic actions of the antidiabetic agent metformin reportedly occur via the activation of the AMP-activated protein kinase ( AMPK) in the heart and other tissues in the presence or absence of changes in cellular energy status. In this study, we tested the hypothesis that metformin has AMPK-independent effects on metabolism in heart muscle. Fatty acid oxidation and glucose utilization ( glycolysis and glucose uptake) were measured in isolated working hearts from halothane-anesthetized male Sprague-Dawley rats and in cultured heart-derived H9c2 cells in the absence or in the presence of metformin ( 2 mM). Fatty acid oxidation and glucose utilization were significantly altered by metformin in hearts and H9c2 cells. AMPK activity was not measurably altered by metformin in either model system, and no impairment of energetic state was observed in the intact hearts. Furthermore, the inhibition of AMPK by 6-[4-(2-piperidin-1-ylethoxy)phenyl]-3- pyridin-4-yl-pyyrazolo[1,5-a]pyrimidine ( Compound C), a well-recognized pharmacological inhibitor of AMPK, or the overexpression of a dominant-negative form of AMPK failed to prevent the metabolic actions of metformin in H9c2 cells. The exposure of H9c2 cells to inhibitors of p38 mitogen-activated protein kinase ( p38 MAPK) or protein kinase C (PKC) partially or completely abrogated metformin-induced alterations in metabolism in these cells, respectively. Thus the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms.