Limitation of p38/MAPK activation by daily normoxic aeration protects chronic hypoxic

Infants with congenital cyanotic heart defects have their hearts chronically perfused with hypoxemic blood. Extracorporal circulation exposes their hearts to reoxygenation injury. We are interested to study the implication of Mitogen-Activated Protein Kinases (MAPK) in chronic hypoxia (CH) and sudden reoxygenation. CH was induced in adult rats by using normobaric hypoxic chambers (FIO2=0.10, 15 days). Myocardial activation of the 3 major MAPKs : c-Jun N-terminal Kinase (JNK), Extracellular signal Regulated Kinase (ERK) and p38, cardiac cell apoptosis and ventricular performance were analysed in isolated perfused hearts. We have shown that CH was associated with increased of p38 activation (p<0.05) and impaired ventricular performance upon reoxygenation (p<0.01). Daily normoxic aeration of CH rats suppressed p38 activation, enhanced ERK and JNK activity (p<0.05), and fully restored functional recovery upon reoxygenation. In vivo p38 inhibition by either SB203580 or SB202190 restored posthypoxic functional recovery in CH hearts. Moreover, daily normoxic aeration decreased the number of apoptotic cells in CH hearts (p<0.05). In conclusion, we have demonstrated that the protective effect of daily normoxic aeration involves modulation of p38 activation. These results have clinical implications for prevention of reoxygenation injury in cyanotic children undergoing cardiac surgery.