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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents

ID: 275458.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
Downregulation of apoptosis-inducing factor in harlequin mutant mice sensitizes the myocardium to oxidative stress-related cell death and pressure overload-induced decompensation
Authors:van Empel, V. P.; Bertrand, A. T.; van der Nagel, R.; Kostin, S.; Doevendans, P. A.; Crijns, H. J.; de Wit, E.; Sluiter, W.; Ackerman, S. L.; De Windt, L. J.
Date of Publication (YYYY-MM-DD):2005-06-24
Title of Journal:Circ Res
Journal Abbrev.:Circ Res
Issue / Number:12
Start Page:e92
End Page:e101
Audience:Not Specified
Abstract / Description:Apoptosis-inducing factor (AIF), or programmed cell death 8 (Pdcd8), is a highly conserved, ubiquitous flavoprotein localized in the mitochondrial intermembrane space. In vivo, AIF provides protection against neuronal apoptosis induced by oxidative stress. Conversely, in vitro, AIF has been demonstrated to have a proapoptotic role when, on induction of the mitochondrial death pathway, AIF translocates to the nucleus where it facilitates chromatin condensation and large scale DNA fragmentation. To determine the role of AIF in myocardial apoptotic processes, we examined cardiomyocytes from an AIF-deficient mouse mutant, Harlequin (Hq). Hq mutant cardiomyocytes demonstrated increased sensitivity to H2O2-induced cell death. Further, Hq hearts subjected to ischemia/reperfusion revealed more cardiac damage and, unlike wild-type mice, the amount of damage increased with the age of the animal. Aortic banding caused enhanced hypertrophy, increased cardiomyocyte apoptotic and necrotic cell death, and accelerated progression toward maladaptive left ventricular remodeling in Hq mutant mice compared with wild-type counterparts. These findings correlated with a reduced capacity of subsarcolemmal mitochondria from Hq mutant hearts to scavenge free radicals. Together, these data demonstrate a critical role for AIF as a cardiac antioxidant in the protection against oxidative stress-induced cell death and development of heart failure induced by pressure overload.
Free Keywords:Animals *Apoptosis Apoptosis Inducing Factor Biomechanics Cells, Cultured Down-Regulation Female Fibrosis Flavoproteins/genetics/*physiology Heart Failure, Congestive/*etiology Hydrogen Peroxide/pharmacology Male Membrane Proteins/deficiency/genetics/*physiology Mice Mice, Mutant Strains Myocardial Reperfusion Injury/etiology Myocardium/metabolism/*pathology *Oxidative Stress RNA, Small Interfering/pharmacology Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Ventricular Remodeling
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
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