Document Detail

EUK-8, a superoxide dismutase and catalase mimetic, reduces cardiac oxidative stress and ameliorates pressure overload-induced heart failure in the harlequin mouse mutant.
MedLine Citation:
PMID:  16904556     Owner:  NLM     Status:  MEDLINE    
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.
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-07-25
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  48     ISSN:  1558-3597     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-08-14     Completed Date:  2006-09-21     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  824-32     Citation Subset:  AIM; IM    
Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, Utrecht, The Netherlands.
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MeSH Terms
Antioxidants / physiology
Apoptosis Inducing Factor / genetics*,  physiology*
Blood Pressure
Ethylenediamines / pharmacology*
Heart Failure / physiopathology,  prevention & control*
Mitochondria / physiology
Myocardium / pathology
Organometallic Compounds / pharmacology*
Oxidative Stress*
Reactive Oxygen Species
Survival Analysis
Grant Support
Reg. No./Substance:
0/Antioxidants; 0/Apoptosis Inducing Factor; 0/Ethylenediamines; 0/Organometallic Compounds; 0/Pdcd8 protein, mouse; 0/Reactive Oxygen Species; 53177-12-1/N,N'-bis(salicylideneamino)ethane-manganese(II)

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