Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies

Journal of Translational Medicine

Hartmut Ruetten³  Ulrich Werner³  Daniel Crowther³  Sibylle Hess³  Jochen Huber¹  Dominik Linz²  Thomas Hübschle³  Wolfgang Linz³  Paulus Wohlfart³ 

[1] Current Adress: Boehringer-Ingelheim Pharma GmbH, CMDR, Biberach a.d.R., Germany;Faculty of Medicine, Saarland University, Saarbrücken, Homburg/Saar, Germany;Sanofi R&D Diabetes Division, Industriepark Hoechst, H825, 65926, Frankfurt/Main, Germany

关键词: Pre-clinical models;    Cardiac dysfunction;    Myocardial ischemia-reperfusion;    Cardioprotection;    Macrovascular risk;    Diabetes;    GLP1-receptor agonist;    Lixisenatide;   

Others  :  827841
DOI  :  10.1186/1479-5876-11-84

 received in 2012-11-30, accepted in 2013-03-20,  发布年份 2013

【 摘 要 】

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)

【 授权许可】

   
2013 Wohlfart et al.; licensee BioMed Central Ltd.

【 图 表 】

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