Reperfusion‐induced myocardial dysfunction is prevented by endogenous annexin‐ A 1 and its N ‐terminal‐derived peptide A c‐ ANX ‐ A 1 2‐26

• Published in: British journal of pharmacology Vol. 168; no. 1; pp. 238 - 252
• Main Authors: Qin, Chengxue, Buxton, Keith D, Pepe, Salvatore, Cao, Anh H, Venardos, Kylie, Love, Jane E, Kaye, David M, Yang, Yuan H, Morand, Eric F, Ritchie, Rebecca H
• Format: Journal Article
• Language: English
• Published: 01.01.2013
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2012.02176.x

BACKGROUND AND PURPOSE Annexin‐ A 1 ( ANX ‐ A 1) is an endogenous, glucocorticoid‐regulated anti‐inflammatory protein. The N ‐terminal‐derived peptide A c‐ ANX ‐ A 1 2–26 preserves cardiomyocyte viability, but the impact of ANX ‐ A 1‐peptides on cardiac contractility is unknown. We now test the hypothesis that ANX ‐ A 1 preserves post‐ischaemic recovery of left ventricular ( LV ) function. EXPERIMENTAL APPROACH A c‐ ANX ‐ A 1 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 ‐ A 1 ( ANX ‐ A 1 –/– ). Myocardial viability and recovery of LV function were determined. KEY RESULTS Ischaemia–reperfusion markedly impaired both cardiomyocyte viability and recovery of LV function by 60%. Treatment with exogenous A c‐ ANX ‐ A 1 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. A c‐ ANX ‐ A 1 2–26 cardioprotection was abolished by either formyl peptide receptor ( FPR )‐nonselective or FPR 1‐selective antagonists, B oc2 and cyclosporin H, but was relatively insensitive to the FPR 2‐selective antagonist QuinC 7. ANX ‐ A 1‐induced cardioprotection was associated with increased phosphorylation of the cell survival kinase A kt. ANX ‐ A 1 −/− exaggerated impairment of post‐ischaemic recovery of LV function, in addition to selective LV FPR 1 down‐regulation. CONCLUSIONS AND IMPLICATIONS These data represent the first evidence that ANX ‐ A 1 affects myocardial function. Our findings suggest ANX ‐ A 1 is an endogenous regulator of post‐ischaemic recovery of LV function. Furthermore, the ANX ‐ A 1‐derived peptide A c‐ ANX ‐ A 1 2–26 on reperfusion rescues LV function, probably via activation of FPR 1. ANX ‐ A 1‐based therapies may thus represent a novel clinical approach for the prevention and treatment of myocardial reperfusion injury.