| EUK-8, a superoxide dismutase and catalase mimetic, reduces cardiac oxidative stress and ameliorates pressure overload-induced heart failure in the harlequin mouse mutant. | |
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MedLine Citation:
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PMID: 16904556 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2006-07-25 |
Journal Detail:
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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:
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Created Date: 2006-08-14 Completed Date: 2006-09-21 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8301365 Medline TA: J Am Coll Cardiol Country: United States |
Other Details:
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Languages: eng Pagination: 824-32 Citation Subset: AIM; IM |
Affiliation:
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Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, Utrecht, The Netherlands. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antioxidants / physiology Apoptosis Apoptosis Inducing Factor / genetics*, physiology* Biomechanics 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 |
| Grant Support | |
ID/Acronym/Agency:
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AG19358/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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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) |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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