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

INTERNATIONAL JOURNAL OF CARDIOLOGY

卷:179

Article

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, Daria⁴  Ferreira, Julio C. B.¹ 

[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

关键词: Myocardial infarction;    4-Hydroxynonenal;    Oxidative stress;    Bioenergetics;    Aldehyde dehydrogenase 2;   

DOI  :  10.1016/j.ijcard.2014.10.140

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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