title: Reperfusion-induced myocardial dysfunction is prevented by endogenous annexin-A1 and its N-terminal-derived peptide Ac-ANX-A1(2-26).
abstract: OBJECTIVE
  Annexin-A1 (ANX-A1) is an endogenous, glucocorticoid-regulated anti-inflammatory protein. The N-terminal-derived peptide Ac-ANX-A1(2-26) preserves cardiomyocyte viability, but the impact of ANX-A1-peptides on cardiac contractility is unknown. We now test the hypothesis that ANX-A1 preserves post-ischaemic recovery of left ventricular (LV) function.
  
  
  METHODS
  Ac-ANX-A1(2-26) was administered on reperfusion, to adult rat cardiomyocytes as well as hearts isolated from rats, wild-type mice and mice deficient in endogenous ANX-A1 (ANX-A1(-/-)). Myocardial viability and recovery of LV function were determined.
  
  
  RESULTS
  Ischaemia-reperfusion markedly impaired both cardiomyocyte viability and recovery of LV function by 60%. Treatment with exogenous Ac-ANX-A1(2-26) at the onset of reperfusion prevented cardiomyocyte injury and significantly improved recovery of LV function, in both intact rat and wild-type mouse hearts. Ac-ANX-A1(2-26) cardioprotection was abolished by either formyl peptide receptor (FPR)-nonselective or FPR1-selective antagonists, Boc2 and cyclosporin H, but was relatively insensitive to the FPR2-selective antagonist QuinC7. ANX-A1-induced cardioprotection was associated with increased phosphorylation of the cell survival kinase Akt. ANX-A1(-/-) exaggerated impairment of post-ischaemic recovery of LV function, in addition to selective LV FPR1 down-regulation.
  
  
  CONCLUSIONS
  These data represent the first evidence that ANX-A1 affects myocardial function. Our findings suggest ANX-A1 is an endogenous regulator of post-ischaemic recovery of LV function. Furthermore, the ANX-A1-derived peptide Ac-ANX-A1(2-26) on reperfusion rescues LV function, probably via activation of FPR1. ANX-A1-based therapies may thus represent a novel clinical approach for the prevention and treatment of myocardial reperfusion injury.
authors.affiliation: Baker IDI Heart & Diabetes Institute, Melbourne, Australia.
authors.forename: Chengxue
authors.initials: C
authors.lastname: Qin
authors.forename: Keith D
authors.initials: KD
authors.lastname: Buxton
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pepe
authors.forename: Anh H
authors.initials: AH
authors.lastname: Cao
authors.forename: Kylie
authors.initials: K
authors.lastname: Venardos
authors.forename: Jane E
authors.initials: JE
authors.lastname: Love
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
authors.forename: Yuan H
authors.initials: YH
authors.lastname: Yang
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Ritchie
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*
chemical_list: C584788:Ac-ANX-A1(2-26) peptide; D017305:Annexin A1; D002316:Cardiotonic Agents; D010446:Peptide Fragments