Adenosine A1 and A3 receptor agonists reduce hypoxic injury through the involvement of P38 MAPK

D. Leshem-Lev, E. Hochhauser, B. Chanyshev, A. Isak, A. Shainberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Activation of either the A1 adenosine receptor (A1R) or the A3 adenosine receptor (A3R), by their specific agonists CCPA and Cl-IB-MECA, respectively, protects cardiac cells in culture against ischemic injury. Yet the full protective mechanism remains unclear. In this study, we therefore examined the involvement of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK) phosphorylation in this protective intracellular signaling mechanism. Furthermore, we investigated whether p38 MAPK phosphorylation occurs upstream or downstream from the opening of mitochondrial ATP-sensitive potassium (K ATP) channels. The role of p38 MAPK activation in the intracellular signaling process was studied in cultured cardiomyocytes subjected to hypoxia, that were pretreated with CCPA or Cl-IB-MECA or diazoxide (a mitochondrial KATP channel opener) with and without SB203580 (a specific inhibitor of phosphorylated p38 MAPK). Cardiomyocytes were also pretreated with anisomycin (p38 MAPK activator) with and without 5-hydroxy decanoic acid (5HD) (a mitochondrial KATP channel blocker). SB203580 together with the CCPA, Cl-IB-MECA or diazoxide abrogated the protection against hypoxia as shown by the level of ATP, lactate dehydrogenase (LDH) release, and propidium iodide (PI) staining. Anisomycin protected the cardiomyocytes against ischemic injury and this protection was abrogated by SB203580 but not by 5HD. Conclusions Activation of A1R or A3R by CCPA or Cl-IB-MECA, respectively, protects cardiomyocytes from hypoxia via phosphorylation of p38 MAPK, which is located downstream from the mitochondrial KATP channel opening. Elucidating the signaling pathway by which adenosine receptor agonists protect cardiomyocytes from hypoxic damage, will facilitate the development of anti ischemic drugs.

Original languageEnglish
Pages (from-to)153-160
Number of pages8
JournalMolecular and Cellular Biochemistry
Issue number1-2
StatePublished - Dec 2010


  • Adenosine receptor agonists
  • Cardiac cell cultures
  • Cardioprotection
  • Hypoxia
  • Ischemia
  • K channels
  • P38 MAPK


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