Urocortin inhibits Beclin1-mediated autophagic cell death in cardiac myocytes exposed to ischaemia/reperfusion injury.
Autophagy is known to be a feature of cardiomyopathies and chronic ischaemia. Here we demonstrate that autophagy is also induced by a single cycle of ischaemia/reperfusion (I/R in neonatal and adult rat cardiac myocytes). Consistent with the critical role for Beclin1 in autophagocytosis, reduction of Beclin1 expression in cardiac myocytes by RNAi reduces I/R-induced autophagy and this is associated with enhanced cell survival. Autophagy is also reduced by urocortin, an endogenous cardiac peptide which we have previously shown to reduce other forms of myocyte cell death induced by I/R. The inhibition of autophagy by urocortin is mediated in part by inhibition of Beclin1 expression, an effect which is mediated by activation of the PI3 kinase/Akt pathway but which does not involve activation of p42/p44 MAPK.
Valentim
Lauren
L
Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
Laurence
Kevin M
KM
Townsend
Paul A
PA
Carroll
Christopher J
CJ
Soond
Surinder
S
Scarabelli
Tiziano M
TM
Knight
Richard A
RA
Latchman
David S
DS
Stephanou
Anastasis
A
D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D002470:Cell Survival / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D015870:Gene Expression; D015428:Myocardial Reperfusion Injury / Q000139:chemically induced* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D054832:Urocortins
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone; D019869:Phosphatidylinositol 3-Kinases