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PRECLINICAL STUDY

EUK-8, a Superoxide Dismutase and Catalase Mimetic, Reduces Cardiac Oxidative Stress and Ameliorates Pressure Overload-Induced Heart Failure in the Harlequin Mouse Mutant

Vanessa P.M. van Empel, MD^_*, Anne T. Bertrand, PhD^_*, Ralph J. van Oort, MSc^_*, Roel van der Nagel, BS^_*, Markus Engelen, MD, Harold V. van Rijen, PhD, Pieter A. Doevendans, MD, PhD, Harry J. Crijns, MD, PhD, Susan L. Ackerman, PhD^||, Wim Sluiter, PhD^¶ and Leon J. De Windt, PhD^_*,_*

^_* Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, Utrecht, the Netherlands
Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands
Heart Lung Center Utrecht, University Medical Center Utrecht, Utrecht, the Netherlands
Department of Cardiology, University Hospital Maastricht, Maastricht, the Netherlands
^|| Howard Hughes Medical Institute, Jackson Laboratory, Bar Harbor, Maine
^¶ Departments of Biochemistry and Genetics, Erasmus Medical Center, Rotterdam, the Netherlands

Manuscript received October 17, 2005; revised manuscript received February 1, 2006, accepted February 28, 2006.

^_* Reprint requests and correspondence: 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. (Email: dewindt{at}niob.knaw.nl).

OBJECTIVES: The purpose of this study was to identify apoptosis-inducing factor (AIF) as a cardiac mitochondrial antioxidant and assess the efficacy of EUK-8, a salen-manganese catalytic free radical scavenger, to protect the AIF-deficient myocardium against pressure overload.

BACKGROUND: Oxidative stress has been postulated to provoke cell death and pathologic remodeling in heart failure. We recently characterized the apoptosis-inducing factor-deficient harlequin (Hq) mouse mutant to display excessive pressure overload-induced oxidative stress, cell death, accelerated progression to heart failure, and a reduced capacity of subsarcolemmal mitochondria to scavenge free radicals, suggesting a role for AIF as a novel mitochondrial antioxidant.

METHODS: Oxidative stress-sensitized Hq mutant mice and their wild-type (WT) counterparts were given low-dose EUK-8 (25 mg/kg/day), an antioxidant with superoxide dismutase, catalase, and oxyradical scavenging properties, or vehicle for 4 weeks, and subjected to pressure overload (transverse aortic constriction) for 4 weeks. Myocardial geometry and function was serially assessed by echocardiography.

RESULTS: EUK-8 ameliorated survival in Hq and WT mice subjected to pressure overload. EUK-8 also improved left ventricular end-systolic dimensions and fractional shortening, prevented myocardial oxidant stress, attenuated necrotic and apoptotic cell death, and attenuated cardiac hypertrophy and fibrosis in both mutant and WT mice.

CONCLUSIONS: The protection against pressure overload-induced heart failure in Hq mice by EUK-8 substantiates the notion that AIF functions as an important mitochondrial antioxidant in the heart. Furthermore, because antioxidant treatment protected both the oxidative stress-prone Hq mouse model and WT mice against pressure overload-induced maladaptive left ventricular remodeling and cardiac decompensation, it may be useful as a novel therapeutic tool in the treatment of human heart failure.

Abbreviations and Acronyms   AIF = apoptosis-inducing factor   DNA = deoxyribonucleic acid   DHE = dihydroethidium   FS = fractional shortening   Hq = harlequin   LVID = left ventricular internal dimension   ·O2– = superoxide anion   ROS = reactive oxygen species   SOD = superoxide dismutase   TAC = transverse aortic banding   WT = wild-type

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