Katia M S Gomes1, Luiz R G Bechara1, Vanessa M Lima1, Márcio A C Ribeiro1, Juliane C Campos1, Paulo M Dourado2, Alicia J Kowaltowski3, Daria Mochly-Rosen4, Julio C B Ferreira5. 1. Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Brazil. 2. Heart Institute, University of Sao Paulo, Brazil. 3. Departamento de Bioquímica, Instituto de Química, Universidade de Sao Paulo, Brazil. 4. Department of Chemical & Systems Biology, Stanford University School of Medicine, Stanford, USA. 5. Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Brazil. Electronic address: jcesarbf@usp.br.
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 24h 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.
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 24h after permanent LAD occlusion surgery) prevented aldehydic overload, mitochondrial dysfunction and improved ventricular function in post-MI cardiomyopathyrats. 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.
Authors: A L Bulteau; K C Lundberg; K M Humphries; H A Sadek; P A Szweda; B Friguet; L I Szweda Journal: J Biol Chem Date: 2001-05-25 Impact factor: 5.157
Authors: Cintia B Ueta; Katia S Gomes; Márcio A Ribeiro; Daria Mochly-Rosen; Julio C B Ferreira Journal: Pharmacol Res Date: 2016-11-19 Impact factor: 7.658
Authors: Juliane C Campos; Luiz H M Bozi; Luiz R G Bechara; Vanessa M Lima; Julio C B Ferreira Journal: Front Physiol Date: 2016-10-21 Impact factor: 4.566