Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: benefits of Alda-1.
Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: benefits of Alda-1.
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心肌梗死后心肌病进展过程中的醛负荷和醛脱氢酶 2 谱：Alda-1 的益处。
DOI：
10.1016/j.ijcard.2014.10.140
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发表时间：
2015-01-20
影响因子：
3.5
通讯作者：
Ferreira, Julio C. B.
中科院分区：
文献类型：
--
作者：
Gomes, Katia M. S.;Bechara, Luiz R. G.;Lima, Vanessa M.;Ribeiro, Marcio A. C.;Campos, Juliane C.;Dourado, Paulo M.;Kowaltowski, Alicia J.;Mochly-Rosen, Daria;Ferreira, Julio C. B.
我们之前证明，通过乙醛脱氢酶 2 (ALDH2)（一种负责代谢主要脂质过氧化产物的线粒体酶）减少心脏醛负荷，可预防急性缺血/再灌注损伤和慢性心力衰竭。然而，心肌梗死后 (MI 后) 心肌病进展过程中 ALDH2 谱、醛负荷和线粒体生物能学的时间依赖性变化尚不清楚，应确定药物治疗的最佳时间窗。在此，我们对大鼠冠状动脉左前降支 (LAD) 永久闭塞后 4 周内的心脏 ALDH2 活性和表达、脂质过氧化、4-羟基-2-壬烯醛 (4-HNE) 加合物形成、谷胱甘肽池和线粒体能量代谢以及 H2O2 释放进行了表征。我们观察到 MI 后心肌病进展过程中心脏线粒体功能持续受到破坏，其特征是线粒体呼吸控制比降低 50% 以上，H2O2 释放增加高达 2 倍。线粒体功能障碍伴随着心脏和循环脂质过氧化物和 4-HNE 蛋白加合物的积累以及电子传递链复合物 I 和 V 的下调。此外，醛负荷增加与心脏 ALDH2 活性降低 90% 和谷胱甘肽库增加相关。进一步支持 ALDH2 机制，持续的 Alda-1 治疗（永久性 LAD 闭塞手术后 24 小时开始）可预防 MI 后心肌病大鼠的醛超载、线粒体功能障碍并改善心室功能。总而言之，我们的研究结果表明，在心室功能障碍的进展过程中，线粒体代谢受到破坏，并且心脏 ALDH2 介导的醛清除率不足，这表明 ALDH2 激活剂在心肌梗死后心肌病的进展过程中具有潜在的治疗价值。
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 is unknown and should be established to determine the optimal time window for drug treatment. 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. 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 24hrs after permanent LAD occlusion surgery) prevented aldehydic overload, mitochondrial dysfunction and improved ventricular function in post-MI cardiomyopathy rats. 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.
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影响因子：
5
作者：
Ma H;Yu L;Byra EA;Hu N;Kitagawa K;Nakayama KI;Kawamoto T;Ren J
通讯作者：
Ren J
影响因子：
20.1
作者：
Endo, Jin;Sano, Motoaki;Fukuda, Keiichi
通讯作者：
Fukuda, Keiichi
影响因子：
24
作者：
Ma, Heng;Li, Ji;Ren, Jun
通讯作者：
Ren, Jun
影响因子：
10.8
作者：
Gomes, Katia M. S.;Campos, Juliane C.;Ferreira, Julio C. B.
通讯作者：
Ferreira, Julio C. B.
影响因子：
37.8
作者：
Nakamura, K;Kusano, K;Ohe, T
通讯作者：
Ohe, T