title: 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: OBJECTIVE
  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.affiliation: Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, Utrecht, The Netherlands.
authors.forename: Vanessa P M
authors.initials: VP
authors.lastname: van Empel
authors.forename: Anne T
authors.initials: AT
authors.lastname: Bertrand
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: van Oort
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: Markus
authors.initials: M
authors.lastname: Engelen
authors.forename: Harold V
authors.initials: HV
authors.lastname: van Rijen
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Crijns
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ackerman
authors.forename: Wim
authors.initials: W
authors.lastname: Sluiter
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000502:physiology; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000235:genetics* / Q000502:physiology*; D001696:Biomechanical Phenomena; D001794:Blood Pressure; D005029:Ethylenediamines / Q000494:pharmacology*; D005355:Fibrosis; D006333:Heart Failure / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D009942:Organometallic Compounds / Q000494:pharmacology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D016019:Survival Analysis
chemical_list: D000975:Antioxidants; D051033:Apoptosis Inducing Factor; D005029:Ethylenediamines; D009942:Organometallic Compounds; C494830:AIFM1 protein, mouse; D017382:Reactive Oxygen Species; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II)