title: Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies.
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.
  
  
  BACKGROUND
  (ELIXA, ClinicalTrials.gov Identifier: NCT01147250).
authors.affiliation: Sanofi R&D Diabetes Division, Industriepark Hoechst, H825, 65926, Frankfurt/Main, Germany. Paulus.Wohlfart@sanofi.com
authors.forename: Paulus
authors.initials: P
authors.lastname: Wohlfart
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Linz
authors.forename: Thomas
authors.initials: T
authors.lastname: Hübschle
authors.forename: Dominik
authors.initials: D
authors.lastname: Linz
authors.forename: Jochen
authors.initials: J
authors.lastname: Huber
authors.forename: Sibylle
authors.initials: S
authors.lastname: Hess
authors.forename: Daniel
authors.initials: D
authors.lastname: Crowther
authors.forename: Ulrich
authors.initials: U
authors.lastname: Werner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Ruetten
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D000067757:Glucagon-Like Peptide-1 Receptor; D006333:Heart Failure / Q000188:drug therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism; D015398:Signal Transduction; D000077191:Wortmannin; D000067758:Glucagon-Like Peptide-2 Receptor
chemical_list: D000730:Androstadienes; D002316:Cardiotonic Agents; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D000077191:Wortmannin; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor
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