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

Paulus Wohlfart (Lead / Corresponding author), Wolfgang Linz, Thomas Hübschle, Dominik Linz, Jochen Huber, Sibylle Hess, Daniel Crowther, Ulrich Werner, Hartmut Ruetten

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51 Citations (Scopus)
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Abstract

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).

Original languageEnglish
Article number84
Number of pages12
JournalJournal of Translational Medicine
Volume11
Issue number1
DOIs
Publication statusPublished - 28 Mar 2013

Keywords

  • Cardiac dysfunction
  • Cardioprotection
  • Diabetes
  • GLP1-receptor agonist
  • Lixisenatide
  • Macrovascular risk
  • Myocardial ischemia-reperfusion
  • Pre-clinical models

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