Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway.
Urocortin (UCN) is a peptide related to hypothalamic corticotrophin-releasing hormone and binds with high affinity to corticotrophin-releasing hormone receptor-2beta, 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 reoxygenation after simulated hypoxia/ischemia. UCN-mediated cell survival was measured by trypan blue exclusion, 3'-OH end labeling of DNA (TUNEL), annexin V, and fluorescence-activated cell sorting. To explore the mechanisms that 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, with the protective effect being observed when UCN was given either prior to ischemia or at the time of reperfusion after ischemia. This suggests a novel function of UCN as a cardioprotective agent that could act when given after ischemia, at reperfusion.
Brar
B K
BK
Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom.
Jonassen
A K
AK
Stephanou
A
A
Santilli
G
G
Railson
J
J
Knight
R A
RA
Yellon
D M
DM
Latchman
D S
DS
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D020935:MAP Kinase Signaling System; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009203:Myocardial Infarction / Q000188:drug therapy; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D054832:Urocortins
D005419:Flavonoids; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one