Mechanisms of cardiac protection with overexpression of A1 adenosine receptors

Amy R. Lankford, Rachael J. Cerniway, Sara E. Regan, Marguerite M. Crawford, Anne M. Byford, G. Paul Matherne

Research output: Contribution to journalArticlepeer-review

Abstract

Myocardial damage from ischemia/reperfusion injury can be minimized through endogenous protective mechanisms, including activation of A1 adenosine receptors. Transgenic mice with cardiac-specific A1 adenosine receptor overexpression (A1AR 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 A1 receptor-mediated cardioprotection. Activation of p38 MAPK by A1 adenosine receptor stimulation was evaluated in neonatal rat cardiomyocytes subjected to simulated ischemia. A1 activation by cyclopentyladenosine decreased cell death and simultaneously enhanced p38 phosphorylation by simulated ischemia. The role of p38 MAP kinase activation in cardioprotection with A1 adenosine receptor overexpression was evaluated in isolated perfused hearts from A1AR 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 A1AR Trans hearts from 54 ± 1 to 27±7% of maximal and increased final EDP from 10±3 mmHg to 34±8 mmHg. A1 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 A1 receptor overexpression is dependent upon activation of p38 MAPK. These findings suggest that adenosine A1 mediated cardioprotection in transgenic mice involves activation of the p38 MAP kinase cascade.

Original languageEnglish (US)
Pages (from-to)439-446
Number of pages8
JournalDrug Development Research
Volume58
Issue number4
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

Keywords

  • Mitogen-activated protein kinase
  • Myocardial ischemia
  • Signal transduction pathways

ASJC Scopus subject areas

  • Drug Discovery

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