title: Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling.
abstract: OBJECTIVE
  We previously demonstrated that pharmacological activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects the heart against acute ischaemia/reperfusion injury. Here, we determined the benefits of chronic activation of ALDH2 on the progression of heart failure (HF) using a post-myocardial infarction model.
  
  
  RESULTS
  We showed that a 6-week treatment of myocardial infarction-induced HF rats with a selective ALDH2 activator (Alda-1), starting 4 weeks after myocardial infarction at a time when ventricular remodelling and cardiac dysfunction were present, improved cardiomyocyte shortening, cardiac function, left ventricular compliance and diastolic function under basal conditions, and after isoproterenol stimulation. Importantly, sustained Alda-1 treatment showed no toxicity and promoted a cardiac anti-remodelling effect by suppressing myocardial hypertrophy and fibrosis. Moreover, accumulation of 4-hydroxynonenal (4-HNE)-protein adducts and protein carbonyls seen in HF was not observed in Alda-1-treated rats, suggesting that increasing the activity of ALDH2 contributes to the reduction of aldehydic load in failing hearts. ALDH2 activation was associated with improved mitochondrial function, including elevated mitochondrial respiratory control ratios and reduced H2O2 release. Importantly, selective ALDH2 activation decreased mitochondrial Ca(2+)-induced permeability transition and cytochrome c release in failing hearts. Further supporting a mitochondrial mechanism for ALDH2, Alda-1 treatment preserved mitochondrial function upon in vitro aldehydic load.
  
  
  CONCLUSIONS
  Selective activation of mitochondrial ALDH2 is sufficient to improve the HF outcome by reducing the toxic effects of aldehydic overload on mitochondrial bioenergetics and reactive oxygen species generation, suggesting that ALDH2 activators, such as Alda-1, have a potential therapeutic value for treating HF patients.
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, Paulo, Brazil.
authors.forename: Katia M S
authors.initials: KM
authors.lastname: Gomes
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, Paulo, Brazil.
authors.forename: Juliane C
authors.initials: JC
authors.lastname: Campos
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, Paulo, Brazil.
authors.forename: Luiz R G
authors.initials: LR
authors.lastname: Bechara
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Paulo, Brazil.
authors.forename: Bruno
authors.initials: B
authors.lastname: Queliconi
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, Paulo, Brazil.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Lima
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Disatnik
authors.affiliation: Heart Institute, Paulo, Brazil.
authors.forename: Paulo
authors.initials: P
authors.lastname: Magno
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Che-Hong
authors.initials: CH
authors.lastname: Chen
authors.affiliation: School of Physical Education and Sports, University of Sao Paulo, Paulo, Brazil.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Brum
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Paulo, Brazil.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Kowaltowski
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, Paulo, Brazil Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA jcesarbf@usp.br.
authors.forename: Julio C B
authors.initials: JC
authors.lastname: Ferreira
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000201:enzymology; D017208:Rats, Wistar; D016276:Ventricular Function / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D024101:Mitochondrial Proteins; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat
keywords: Bioenergetics; Heart disease; Mitochondria; Oxidant stress; Pharmacological therapy