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J Biol Chem, Vol. 275, Issue 12, 8508-8514, March 24, 2000
From the Urocortin (UCN) is a peptide related to
hypothalamic corticotrophin-releasing hormone and binds with high
affinity to corticotrophin-releasing hormone receptor-2
Urocortin Protects against Ischemic and Reperfusion Injury via a
MAPK-dependent Pathway*
§,
,,,
Institute of Child Health, University
College London, 30 Guilford Street, London WC1N 1EH, the ¶ Hatter
Institute of Cardiology, University College London Hospitals and
Medical School, London WC1E 6DB, and the ** Department of Cystic
Fibrosis, National Heart and Lung Institute, Emmanuel Kaye Building,
Manresa Road, London SW3 6LR, United Kingdom
, 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.
*
This work was supported by the British Heart Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address; Dept. of Medical Physiology, Inst. of Medical
Biology, University of Tromso, Tromso, Norway.
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