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

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Abstract

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 (KATP) 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.

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Acknowledgments

This research study was conducted through the generous support of The Adar Program for the Advancement of Research in Heart Function and the Horowitz Foundation at Bar-Ilan University. The authors are indebted to Avrille Goldreich for helping to prepare and submitting this manuscript for publication.

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Authors and Affiliations

  1. The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, 52900, Israel

    D. Leshem-Lev, B. Chanyshev, A. Isak & A. Shainberg

  2. The Cardiac Research Laboratory of the Cardiothoracic Surgery Department, Rabin Medical Center, Felsenstein Medical Research Center, Tel Aviv University, Petah Tikva, Israel

    E. Hochhauser

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  1. D. Leshem-Lev
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  2. E. Hochhauser
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Correspondence to A. Shainberg.

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Leshem-Lev, D., Hochhauser, E., Chanyshev, B. et al. Adenosine A1 and A3 receptor agonists reduce hypoxic injury through the involvement of P38 MAPK. Mol Cell Biochem 345, 153–160 (2010). https://doi.org/10.1007/s11010-010-0568-5

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  • DOI: https://doi.org/10.1007/s11010-010-0568-5

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