Targeting p38-MAPK in the ischaemic heart: kill or cure?

The p38-MAPK pathway plays an important role in myocardial ischaemia/reperfusion injury and has been implicated in the regulation of cardiac gene expression, myocyte hypertrophy, inflammation, energetic metabolism, contractility, proliferation and apoptosis. The activation of p38-MAPK by dual phosphorylation during myocardial ischaemia aggravates lethal injury. However, under other circumstances activation can protect the heart, and recent evidence suggests that the mechanism of p38-MAPK activation may differ by circumstance. Determining the precise mechanism of activation during myocardial ischaemia is of considerable importance, since it may allow prevention of the detrimental, but not the beneficial, activation of p38-MAPK and lead to the identification of the relevant signalling molecules to be targeted for pharmaceutical intervention.