CRH-like peptides protect cardiac myocytes from lethal ischaemic injury.
Simulated ischaemia causes both necrotic and apoptotic death of primary cultures of neonatal rat cardiac myocytes. Simulated ischaemia is associated with increased expression of urocortin mRNA and with the release of urocortin peptide into the medium. Exogenous urocortin is more potent than corticotropin releasing hormone (CRH) in protecting cardiac myocytes from necrotic and apoptotic death induced by ischaemia, and the cardioprotective effects of ischaemia-preconditioned media are abrogated by antagonists to the CRH family of peptides. Simulated ischaemia increases cardiac myocyte expression of CCAAT enhancer binding (C/EBP) transcription factors, and of the p65 subunit of NFkappaB, and reporter activity of a construct incorporating a fragment of the urocortin promoter containing a C/EBP consensus site is also enhanced by simulated ischaemia. The data suggest that ischaemia, acting partly through increased expression of C/EBP transactivators, increases expression of urocortin mRNA, which is rapidly translated to the mature form. The mature peptide is rapidly released, and exerts autocrine/paracrine protective effects through the cardiac CRH-R2 receptor which preferentially binds urocortin.
Brar
B K
BK
Department of Molecular Pathology, The Windever Institute of Medical Sciences, London, UK.
Stephanou
A
A
Okosi
A
A
Lawrence
K M
KM
Knight
R A
RA
Marber
M S
MS
Latchman
D S
DS
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005434:Flow Cytometry; D020287:In Situ Nick-End Labeling; D017202:Myocardial Ischemia / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054832:Urocortins
D054832:Urocortins; D003346:Corticotropin-Releasing Hormone