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The adenosine A(2A) receptor - Myocardial protectant and coronary target in endotoxemia.
MedLine Citation:
PMID:  22192288     Owner:  NLM     Status:  Publisher    
BACKGROUND: Cardiac injury and dysfunction are contributors to disease progression and mortality in sepsis. This study evaluated the cardiovascular role of intrinsic A(2A) adenosine receptor (A(2A)AR) activity during lipopolysaccharide (LPS)-induced inflammation. METHODS: We assessed the impact of 24h of LPS challenge (20mg/kg, IP) on cardiac injury, coronary function and inflammatory mediator levels in Wild-Type (WT) mice and mice lacking functional A(2A)ARs (A(2A)AR KO). RESULTS: Cardiac injury was evident in LPS-treated WTs, with ~7-fold elevation in serum cardiac troponin I (cTnI), and significant ventricular and coronary dysfunction. Absence of A(2A)ARs increased LPS-provoked cTnI release at 24h by 3-fold without additional demise of contraction function. Importantly, A(2A)AR deletion per se emulated detrimental effects of LPS on coronary function, and LPS was without effect in coronary vessels lacking A(2A)ARs. Effects of A(2A)AR KO were independent of major shifts in circulating C-reactive protein (CRP) and haptoglobin. Cytokine responses were largely insensitive to A(2A)AR deletion; substantial LPS-induced elevations (up to 100-fold) in IFN-γ and IL-10 were unaltered in A(2A)AR KO mice, as were levels of IL-4 and TNF-α. However, late elevations in IL-2 and IL-5 were differentially modulated by A(2A)AR KO (IL-2 reduced, IL-5 increased). Data demonstrate that in the context of LPS-triggered cardiac and coronary injury, A(2A)AR activity protects myocardial viability without modifying contractile dysfunction, and selectively modulates cytokine (IL-2, IL-5) release. A(2A)ARs also appear to be targeted by LPS in the coronary vasculature. CONCLUSIONS: These experimental data suggest that preservation of A(2A)AR functionality might provide therapeutic benefit in human sepsis.
Melissa E Reichelt; Kevin J Ashton; Xing Lin Tan; S Jamal Mustafa; Catherine Ledent; Lea M D Delbridge; Polly A Hofmann; John P Headrick; R Ray Morrison
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-20
Journal Detail:
Title:  International journal of cardiology     Volume:  -     ISSN:  1874-1754     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8200291     Medline TA:  Int J Cardiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier Ireland Ltd.
Heart Foundation Research Center, Griffith University, Southport QLD, Australia; Department of Physiology, University of Melbourne, Parkville VIC, Australia.
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