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Reperfusion‐induced myocardial dysfunction is prevented by endogenous annexin‐ A 1 and its N ‐terminal‐derived peptide A c‐ ANX ‐ A 1 2‐26
Author(s) -
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
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02176.x
Subject(s) - cardioprotection , endogeny , protein kinase b , reperfusion injury , phosphorylation , medicine , annexin a1 , endocrinology , cardiac function curve , contractility , pharmacology , chemistry , annexin , ischemia , apoptosis , heart failure , biochemistry
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.