Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway

Urocortin (UCN) is a peptide related to hypothalamic corticotrophin-releasi ng hormone and binds with high affinity to corticotrophin-releasing hormone receptor-2 beta, which is expressed in the heart. In this study, we report that UCN prevented cell death when administered to primary cardiac myocyte cultures both prior to simulated hypoxia/ischemia and at the point of reox ygenation after simulated hypoxia/ischemia. UCN-mediated cell survival was measured by trypan blue exclusion, 3'-OH end labeling of DNA (TUNEL), annex in V, and fluorescence-activated cell sorting. To explore the mechanisms th at could be responsible for this effect, we investigated the involvement of MAPK-dependent pathways. UCN caused rapid phosphorylation of ERK1/2-p42/44 , and PD98059, which blocks the MEK1-ERK1/2-p42/44 cascade, also inhibited the survival-promoting effect of UCN. Most important, UCN reduced damage in isolated rat hearts ex vivo subjected to regional ischemia/reperfusion, wi th the protective effect being observed when UCN was given either prior to ischemia or at the time of reperfusion after ischemia. This suggests a nove l function of UCN as a cardioprotective agent that could act when given aft er ischemia, at reperfusion.