P38 MAPK is involved in adenosine receptors' protection against ischemia–reperfusion (I/R) injury of the heart

Abstract

A1 adenosine receptor (A1R) or A3 adenosine receptor (A3R) activation elicits I/R protection. We investigated (1) the effects of preischemic adenosine A1R (CCPA) or A3R (Cl-IB-MECA) activation on the I/R recovery of normal WKY and hypertrophied SHR hearts. (2) p38 MAPK activation in this process (3) whether p38 phosphorylation occurs upstream or downstream from the opening of mitochondrial KATP channels. WKY and SHR animals were injected 24 h before the experiment with 100 μg/kg CCPA or Cl-IB-MECA. Isolated rat hearts were subjected to I/R (30 min). The intracellular protection mechanism was studied in cultured cardiomyocytes incubated with CCPA, or Cl-IB-MECA or diazoxide (mitochondrial KATP channels opener) with and without SB203580 for 15 min prior to 90 min hypoxia. Both A1R and A3R agonists reduced hypoxia-induced injury in vivo and in vitro. In the WKY hearts, phosphorylated p38 appeared only in hearts pretreated with CCPA or Cl-IB-MECA. In SHR hearts, phosphorylation was observed in all groups, with the additive effects of adenosine treatment, mostly in A3R activation. This protection was prevented when cultured cardiomyocytes were treated with SB203580 together with either CCPA or Cl-IB-MECA, or diazoxide, as revealed by LDH release, ATP content and mitochondrial membrane potentials. CCPA and Cl-IB-MECA reduced I/R damage in normal and particularly hypertrophied hearts. This protection was partially related to the increased phosphorylation of p38 MAPK, which is located downstream from mitochondrial KATP channels opening.