title: ER stress contributes to ischemia-induced cardiomyocyte apoptosis.
abstract: Myocardial ischemia is a severe stress condition that leads to loss of cardiomyocytes. The cell loss is attributed to apoptosis, although the exact mechanisms involved are only partially defined, which limits therapeutic opportunities. Here, we show caspase activation and apoptosis in neonatal rat cardiomyocyte cultures subjected to simulated ischemia by serum, glucose, and oxygen deprivation (SGO). Caspase activation was preceded by endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR), detected by the induction of Grp78, induction and splicing of XBP1, and phosphorylation of eukaryotic initiation factor 2-alpha (eIF2alpha). At a later time the ER stress response switched from UPR and cytoprotective response to a pro-apoptotic response as demonstrated by the upregulation of CHOP and processing of pro-caspase-12. Thus, we provide evidence that the ER can generate and propagate apoptotic signals in response to ischemic stress and this pathway is therefore a novel target for prevention of ischemia-mediated cardiomyocyte loss.
authors.affiliation: Department of Biochemistry, National University of Ireland, Galway, Ireland.
authors.forename: Eva
authors.initials: E
authors.lastname: Szegezdi
authors.forename: Angela
authors.initials: A
authors.lastname: Duffy
authors.forename: Martin E
authors.initials: ME
authors.lastname: O'Mahoney
authors.forename: Susan E
authors.initials: SE
authors.lastname: Logue
authors.forename: Louise A
authors.initials: LA
authors.lastname: Mylotte
authors.forename: Timothy
authors.initials: T
authors.lastname: O'brien
authors.forename: Afshin
authors.initials: A
authors.lastname: Samali
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology*; D017202:Myocardial Ischemia; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051017:Apoptosis Regulatory Proteins