Myocardial infarction in rats causes partial impairment in insulin response associated with reduced fatty acid oxidation and mitochondrial gene expression
Myocardial infarction in rats causes partial impairment in insulin response associated with reduced fatty acid oxidation and mitochondrial gene expression
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DOI：
10.1016/j.jtcvs.2010.08.003
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发表时间：
2010-11-01
影响因子：
6
通讯作者：
Doenst, Torsten
中科院分区：
文献类型：
--
作者：
Amorim, Paulo A.;Nguyen, T. Dung;Doenst, Torsten
目的：心肌梗死导致心肌收缩功能障碍。在糖尿病患者中，收缩力受损与胰岛素作用丧失和线粒体功能障碍有关。我们评估了结扎左冠状动脉后大鼠的心脏胰岛素敏感性和线粒体及收缩功能。左冠状动脉结扎后2周，我们进行了在体超声心动图检查，评估了离体工作心脏的底物利用和胰岛素反应以及胰岛素的调节作用（Akt，葡萄糖转运蛋白4型）和线粒体信号传导（p38丝裂原活化蛋白激酶，过氧化物酶体增殖物活化受体-γ共激活因子1 α，结果：心肌梗死后心脏扩张，射血分数降低（射血分数< 50%）。基础葡萄糖氧化被保留，但脂肪酸氧化显著减少。胰岛素对底物氧化的作用因脂肪酸氧化的减少和葡萄糖氧化的增加而显著受损。然而，胰岛素刺激的葡萄糖摄取在梗死心脏中是正常的，与正常的胰岛素诱导的Akt磷酸化和葡萄糖转运蛋白4型的mRNA表达不变一致。对胰岛素的氧化反应受损与调节脂肪酸氧化（长链酰基辅酶A脱氢酶、肉毒碱棕榈酰转移酶1、过氧化物酶体增殖物激活受体-α）和线粒体生物合成（线粒体转录因子A）的基因的mRNA表达降低相关。虽然线粒体主调节器过氧化物酶体增殖物激活受体-γ共激活因子1 α的mRNA表达在梗死心脏中是正常的，但其转录后激活因子p38丝裂原激活蛋白激酶的蛋白表达显著降低。大鼠心肌梗死在底物氧化水平引起部分胰岛素抵抗，这与线粒体和心肌收缩功能障碍有关。线粒体功能障碍的特点是氧化脂肪酸的能力降低，可能是由于缺乏p38丝裂原活化蛋白激酶而导致线粒体生物合成受损。（《胸血管外科杂志》2010; 140：1160-7）
Objective: Myocardial infarction leads to contractile dysfunction. In patients with diabetes, impaired contractility has been associated with the loss of insulin effects and mitochondrial dysfunction. We assessed cardiac insulin sensitivity and mitochondrial and contractile function in rats after ligation of the left coronary artery.Methods: At 2 weeks after left coronary artery ligation, we performed echocardiography in vivo and assessed the substrate use and insulin response in the isolated working heart and the regulation of insulin (Akt, glucose transporter type 4) and mitochondrial signaling (p38 mitogen-activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha, mitochondrial transcription factor A) using polymerase chain reaction and Western blotting.Results: The infarcted hearts were dilated and had a reduced ejection fraction (ejection fraction < 50%). The basal glucose oxidation was preserved, but the fatty acid oxidation was significantly reduced. Insulin's effect on substrate oxidation was significantly impaired for both the decrease in fatty acid oxidation and the increase in glucose oxidation. However, insulin-stimulated glucose uptake was normal in the infarcted hearts, consistent with normal insulin-induced phosphorylation of Akt and unchanged mRNA expression of glucose transporter type 4. The impaired oxidative response to insulin was associated with reduced mRNA expression of the genes regulating fatty acid oxidation (long-chain-acyl-coenzyme A dehydrogenase, carnitine palmitoyltransferase 1, peroxisome proliferator-activated receptor-alpha) and mitochondrial biogenesis (mitochondrial transcription factor A). Although mRNA expression of the mitochondrial master regulator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha was normal in the infarcted hearts, the protein expression of its post-transcriptional activator, p38 mitogen-activated protein kinase, was significantly reduced.Conclusions: Myocardial infarction in rats caused partial insulin resistance at the level of substrate oxidation, which was associated with mitochondrial and cardiac contractile dysfunction. Mitochondrial dysfunction was characterized by a reduced capacity to oxidize fatty acids and might have resulted from impaired mitochondrial biogenesis through the lack of p38 mitogen-activated protein kinase. (J Thorac Cardiovasc Surg 2010; 140: 1160-7)