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Reperfusion-Induced Myocardial Dysfunction is Prevented by Endogenous Annexin-A1 And Its N-terminal Derived Peptide Ac-ANX-A1 (2-26).
MedLine Citation:
PMID:  22924634     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY 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 downregulation. CONCLUSIONS AND IMPLICATIONS: These data represent the first evidence that ANX-A1 impacts on 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, likely 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:
Chengxue Qin; Keith D Buxton; Salvatore Pepe; Anh H Cao; Kylie Venardos; Jane E Love; David M Kaye; Yuan H Yang; Eric F Morand; Rebecca H Ritchie
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-24
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-8-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
Affiliation:
Baker IDI Heart & Diabetes Institute, Melbourne, 8008, Australia.
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