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首页> 外文期刊>Journal of Translational Medicine >Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies
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Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies

机译：Lixisenatide在大鼠心肌缺血再灌注损伤研究中的心脏保护作用

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Background Lixisenatide is a glucagon-like peptide-1 analog which stimulates insulin secretion and inhibits glucagon secretion and gastric emptying. We investigated cardioprotective effects of lixisenatide in rodent models reflecting the clinical situation. Methods The acute cardiac effects of lixisenatide were investigated in isolated rat hearts subjected to brief ischemia and reperfusion. Effects of chronic treatment with lixisenatide on cardiac function were assessed in a modified rat heart failure model after only transient coronary occlusion followed by long-term reperfusion. Freshly isolated cardiomyocytes were used to investigate cell-type specific mechanisms of lixisenatide action. Results In the acute setting of ischemia-reperfusion, lixisenatide reduced the infarct-size/area at risk by 36% ratio without changes on coronary flow, left-ventricular pressure and heart rate. Treatment with lixisenatide for 10 weeks, starting after cardiac ischemia and reperfusion, improved left ventricular end-diastolic pressure and relaxation time and prevented lung congestion in comparison to placebo. No anti-fibrotic effect was observed. Gene expression analysis revealed a change in remodeling genes comparable to the ACE inhibitor ramipril. In isolated cardiomyocytes lixisenatide reduced apoptosis and increased fractional shortening. Glucagon-like peptide-1 receptor (GLP1R) mRNA expression could not be detected in rat heart samples or isolated cardiomyocytes. Surprisingly, cardiomyocytes isolated from GLP-1 receptor knockout mice still responded to lixisenatide. Conclusions In rodent models, lixisenatide reduced in an acute setting infarct-size and improved cardiac function when administered long-term after ischemia-reperfusion injury. GLP-1 receptor independent mechanisms contribute to the described cardioprotective effect of lixisenatide. Based in part on these preclinical findings patients with cardiac dysfunction are currently being recruited for a randomized, double-blind, placebo-controlled, multicenter study with lixisenatide. Trial registration (ELIXA, ClinicalTrials.gov Identifier: NCT01147250 )
机译：背景技术Lixisenatide是一种胰高血糖素样肽-1类似物，其刺激胰岛素分泌并抑制胰高血糖素分泌和胃排空。我们调查了Lixisenatide在反映临床情况的啮齿动物模型中的心脏保护作用。方法研究了在短暂的缺血再灌注和再灌注的分离的大鼠心中研究了Lixisenatide的急性心脏作用。在仅瞬时冠状动脉闭塞后，在改性大鼠心力衰竭模型中评估了慢性治疗对心脏功能的慢性治疗的影响，然后进行长期再灌注。新鲜孤立的心肌细胞用于研究Lixisenatide作用的细胞型特异性机制。导致缺血再灌注的急性设定，LixIsenatide将梗死尺寸/面积降低36％的比例，无需冠状动脉源，左心室压力和心率变化。用LixIsenatide治疗10周，开始心脏缺血再灌注并再灌注，改善左心室尿道压力和弛豫时间并预防肺充血与安慰剂相比。没有观察到抗纤维化效应。基因表达分析揭示了与ACE抑制剂Ramipril相当的重塑基因的变化。在孤立的心肌细胞中，Lixisenatide降低了细胞凋亡并增加了分数缩短。胰高血糖素肽-1受体（GLP1R）mRNA表达不能在大鼠心脏样品或分离的心肌细胞中检测到。令人惊讶的是，从GLP-1受体敲除小鼠分离的心肌细胞仍然反应Lixisenatide。结论在啮齿动物模型中，Lixisenatide在急性设定梗死梗死中减少，在缺血再灌注损伤后长期施用时的心脏功能改善。 GLP-1受体的独立机制有助于Lixisenatide的描述的心脏保护作用。部分地基于这些临床前调查结果，目前正在招募用于随机，双盲，安慰剂控制的多中心研究的心脏功能障碍。试用登记（Elixa，ClinicalTrials.gov标识符：NCT01147250）

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