EUK-8, a superoxide dismutase and catalase mimetic, reduces cardiac oxidative stress and ameliorates pressure overload-induced heart failure in the harlequin mouse mutant.

Abstract

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.

• Authors: Vanessa P M van Empel, Anne T Bertrand, Ralph J van Oort, Roel van der Nagel, Markus Engelen, Harold V van Rijen, Pieter A Doevendans, Harry J Crijns, Susan L Ackerman, Wim Sluiter, Leon J De Windt
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 48 Issue 4 Pg. 824-32 (Aug 15 2006) ISSN: 1558-3597 [Electronic] United States
• PMID: 16904556 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Apoptosis Inducing Factor
• Ethylenediamines
• Organometallic Compounds
• Pdcd8 protein, mouse
• Reactive Oxygen Species
• N,N'-bis(salicylideneamino)ethane-manganese(II)

Topics

• Animals
• Antioxidants (physiology)
• Apoptosis
• Apoptosis Inducing Factor (genetics, physiology)
• Biomechanical Phenomena
• Blood Pressure
• Ethylenediamines (pharmacology)
• Fibrosis
• Heart Failure (physiopathology, prevention & control)
• Mice
• Mitochondria (physiology)
• Mutation
• Myocardium (pathology)
• Necrosis
• Organometallic Compounds (pharmacology)
• Oxidative Stress
• Reactive Oxygen Species
• Survival Analysis