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(Circulation Research. 2005;96:e92.)
© 2005 American Heart Association, Inc.

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Downregulation of Apoptosis-Inducing Factor in Harlequin Mutant Mice Sensitizes the Myocardium to Oxidative Stress–Related Cell Death and Pressure Overload–Induced Decompensation

Vanessa P.M. van Empel, Anne T. Bertrand, Roel van der Nagel, Sawa Kostin, Pieter A. Doevendans, Harry J. Crijns, Elly de Wit, Wim Sluiter, Susan L. Ackerman, Leon J. De Windt

From the Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands (V.P.M.v.E., A.T.B., R.v.d.N., L.J.D.W.), Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands; Max-Planck-Institute (S.K.), Bad Nauheim, Germany; Heart Lung Center Utrecht (P.A.D.), the Netherlands; Department of Cardiology (H.J.C.), University Hospital Maastricht, the Netherlands; Department of Biochemistry (E.d.W., W.S.), Erasmus MC, Rotterdam, the Netherlands; and The Jackson Laboratory (S.L.A.), Bar Harbor, Maine.

Correspondence to Dr Leon J. De Windt, Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Arts and Sciences, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. E-mail dewindt{at}niob.knaw.nl

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.

Key Words: apoptosis • heart failure • oxidative stress • apoptosis-inducing factor

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