Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: Benefits of Alda-1

Author(s)

Gomes, Katia M. S. ^[1] ; Bechara, Luiz R. G. ^[1] ; Lima, Vanessa M. ^[1] ; Ribeiro, Marcio A. C. ^[1] ; Campos, Juliane C. ^[1] ; Dourado, Paulo M. ^[2] ; Kowaltowski, Alicia J. ^[3] ; Mochly-Rosen, Daria ^[4] ; Ferreira, Julio C. B. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, BR-05508000 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Heart, BR-05508000 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo - Brazil

^[4] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 - USA

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF CARDIOLOGY; v. 179, p. 129-138, JAN 20 2015.
• Web of Science Citations: 26

Abstract

Background/objectives: 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 24 h after permanent LAD occlusion surgery) prevented aldehydic overload, mitochondrial dysfunction and improved ventricular function in post-MI cardiomyopathy rats. Conclusion: 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. (C) 2014 Elsevier Ireland Ltd. All rights reserved. (AU)

• FAPESP's process: 12/05765-2 - Contribution of aldehyde dehydrogenase 2 to heart failure development
• Grantee: Julio Cesar Batista Ferreira
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 10/51906-1 - Mitochondrial bioenergetics, ion transport, redox state and DNA metabolism
• Grantee: Alicia Juliana Kowaltowski
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC