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Mechanisms of cardiac protection with Overexpression of A 1 adenosine receptors
Author(s) -
Lankford Amy R.,
Cerniway Rachael J.,
Regan Sara E.,
Crawford Marguerite M.,
Byford Anne M.,
Matherne G. Paul
Publication year - 2003
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.10189
Subject(s) - cardioprotection , adenosine , adenosine receptor , adenosine a3 receptor , adenosine a1 receptor , reperfusion injury , ischemia , p38 mitogen activated protein kinases , pharmacology , medicine , mapk/erk pathway , ischemic preconditioning , receptor , kinase , endocrinology , chemistry , microbiology and biotechnology , biology , agonist
Myocardial damage from ischemia/reperfusion injury can be minimized through endogenous protective mechanisms, including activation of A 1 adenosine receptors. Transgenic mice with cardiac‐specific A 1 adenosine receptor overexpression (A 1 AR Trans) have demonstrated functional and metabolic tolerance to in vitro and in vivo myocardial ischemia/reperfusion injury. The purpose of this investigation is to examine the role of p38 MAP kinase in A 1 receptor‐mediated cardioprotection. Activation of p38 MAPK by A 1 adenosine receptor stimulation was evaluated in neonatal rat cardiomyocytes subjected to simulated ischemia. A 1 activation by cyclopentyladenosine decreased cell death and simultaneously enhanced p38 phosphorylation by simulated ischemia. The role of p38 MAP kinase activation in cardioprotection with A 1 adenosine receptor overexpression was evaluated in isolated perfused hearts from A 1 AR Trans mice subjected to 20 min ischemia and 30 min reperfusion. Inhibition of p38 MAPK activity with 10 μM SB‐203580 prior to ischemia and during reperfusion decreased postischemic total functional recovery in A 1 AR Trans hearts from 54 ± 1 to 27±7% of maximal and increased final EDP from 10±3 mmHg to 34±8 mmHg. A 1 adenosine receptor‐mediated activation of p38 MAP kinase in cardiomyocytes is involved in the protection of cells from ischemic death. Tolerance to ischemic injury by A 1 receptor overexpression is dependent upon activation of p38 MAPK. These findings suggest that adenosine A 1 mediated cardioprotection in transgenic mice involves activation of the p38 MAP kinase cascade. Drug Dev. Res. 58:439–446, 2003. © 2003 Wiley‐Liss, Inc.