title: Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: benefits of Alda-1.
abstract: OBJECTIVE
  We previously demonstrated that reducing cardiac aldehydic load by aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme responsible for metabolizing the major lipid peroxidation product, protects against acute ischemia/reperfusion injury and chronic heart failure. However, time-dependent changes in ALDH2 profile, aldehydic load and mitochondrial bioenergetics during progression of post-myocardial infarction (post-MI) cardiomyopathy are unknown and should be established to determine the optimal time window for drug treatment.
  
  
  METHODS
  Here we characterized cardiac ALDH2 activity and expression, lipid peroxidation, 4-hydroxy-2-nonenal (4-HNE) adduct formation, glutathione pool and mitochondrial energy metabolism and H₂O₂ release during the 4 weeks after permanent left anterior descending (LAD) coronary artery occlusion in rats.
  
  
  RESULTS
  We observed a sustained disruption of cardiac mitochondrial function during the progression of post-MI cardiomyopathy, characterized by >50% reduced mitochondrial respiratory control ratios and up to 2 fold increase in H₂O₂ release. Mitochondrial dysfunction was accompanied by accumulation of cardiac and circulating lipid peroxides and 4-HNE protein adducts and down-regulation of electron transport chain complexes I and V. Moreover, increased aldehydic load was associated with a 90% reduction in cardiac ALDH2 activity and increased glutathione pool. Further supporting an ALDH2 mechanism, sustained Alda-1 treatment (starting 24h after permanent LAD occlusion surgery) prevented aldehydic overload, mitochondrial dysfunction and improved ventricular function in post-MI cardiomyopathy rats.
  
  
  CONCLUSIONS
  Taken together, our findings demonstrate a disrupted mitochondrial metabolism along with an insufficient cardiac ALDH2-mediated aldehyde clearance during the progression of ventricular dysfunction, suggesting a potential therapeutic value of ALDH2 activators during the progression of post-myocardial infarction cardiomyopathy.
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Brazil.
authors.forename: Katia M S
authors.initials: KM
authors.lastname: Gomes
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Brazil.
authors.forename: Luiz R G
authors.initials: LR
authors.lastname: Bechara
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Brazil.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Lima
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Brazil.
authors.forename: Márcio A C
authors.initials: MA
authors.lastname: Ribeiro
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Brazil.
authors.forename: Juliane C
authors.initials: JC
authors.lastname: Campos
authors.affiliation: Heart Institute, University of Sao Paulo, Brazil.
authors.forename: Paulo M
authors.initials: PM
authors.lastname: Dourado
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de Sao Paulo, Brazil.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Kowaltowski
authors.affiliation: Department of Chemical & Systems Biology, Stanford University School of Medicine, Stanford, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.affiliation: Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Brazil. Electronic address: 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; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D009202:Cardiomyopathies / Q000188:drug therapy / Q000378:metabolism*; D018450:Disease Progression; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000447:Aldehydes; D001549:Benzamides; D052117:Benzodioxoles; D024101:Mitochondrial Proteins; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat
keywords: 4-Hydroxynonenal; Aldehyde dehydrogenase 2; Bioenergetics; Myocardial infarction; Oxidative stress