title: Calcineurin Abeta gene targeting predisposes the myocardium to acute ischemia-induced apoptosis and dysfunction.
abstract: Cardiovascular disease is the leading cause of mortality and morbidity within the industrialized nations of the world, with coronary heart disease (CHD) accounting for as much as 66% of these deaths. Acute myocardial infarction is a typical sequelae associated with long-standing coronary heart disease resulting in large scale loss of ventricular myocardium through both apoptotic and necrotic cell death. In this study, we investigated the role that the calcium calmodulin-activated protein phosphatase calcineurin (PP2B) plays in modulating cardiac apoptosis after acute ischemia-reperfusion injury to the heart. Calcineurin Abeta gene-targeted mice showed a greater loss of viable myocardium, enhanced DNA laddering and TUNEL, and a greater loss in functional performance compared with strain-matched wild-type control mice after ischemia-reperfusion injury. RNA expression profiling was performed to uncover potential mechanisms associated with this loss of cardioprotection. Interestingly, calcineurin Abeta-/- hearts were characterized by a generalized downregulation in gene expression representing approximately 6% of all genes surveyed. Consistent with this observation, nuclear factor of activated T cells (NFAT)-luciferase reporter transgenic mice showed reduced expression in calcineurin Abeta-/- hearts at baseline and after ischemia-reperfusion injury. Finally, expression of an activated NFAT mutant protected cardiac myocytes from apoptotic stimuli, whereas directed inhibition of NFAT augmented cell death. These results represent the first genetic loss-of-function data showing a prosurvival role for calcineurin-NFAT signaling in the heart.
authors: Department of Pediatrics, Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
authors: Orlando F
authors: OF
authors: Bueno
authors: Daniel J
authors: DJ
authors: Lips
authors: Robert A
authors: RA
authors: Kaiser
authors: Benjamin J
authors: BJ
authors: Wilkins
authors: Yan-Shan
authors: YS
authors: Dai
authors: Betty J
authors: BJ
authors: Glascock
authors: Raisa
authors: R
authors: Klevitsky
authors: Timothy E
authors: TE
authors: Hewett
authors: Thomas R
authors: TR
authors: Kimball
authors: Bruce J
authors: BJ
authors: Aronow
authors: Pieter A
authors: PA
authors: Doevendans
authors: Jeffery D
authors: JD
authors: Molkentin
mesh_terms: D000818:Animals; D017209:Apoptosis; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D020869:Gene Expression Profiling; D018390:Gene Targeting; D006321:Heart / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D019703:Calcineurin