Journal
INTERNATIONAL JOURNAL OF CARDIOLOGY
Volume 179, Issue -, Pages 129-138Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.ijcard.2014.10.140
Keywords
Myocardial infarction; 4-Hydroxynonenal; Oxidative stress; Bioenergetics; Aldehyde dehydrogenase 2
Categories
Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Sao Paulo (FAPESP) [2012/05765-2, 2010/51906-1, 2013/07937-8]
- Conselho Nacional de Pesquisa e Desenvolvimento Brasil (CNPq) [470880/2012-0, 301105/2012-0, 407306/2013-7, 302898/2013-1, 573530/2008-4]
- National Institutes of Health [NIAAA 11147]
- FAPESP
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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.
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