Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling
Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling
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DOI：
10.1093/cvr/cvu125
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发表时间：
2014-09-01
影响因子：
10.8
通讯作者：
Ferreira, Julio C. B.
中科院分区：
文献类型：
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作者：
Gomes, Katia M. S.;Campos, Juliane C.;Ferreira, Julio C. B.
目的：我们以前证明，药理学激活线粒体醛脱氢酶2（ALDH 2）保护心脏免受急性缺血/再灌注损伤。在这里，我们使用心肌梗死后模型确定了ALDH 2慢性激活对心力衰竭（HF）进展的益处。方法和结果我们表明，在心肌梗死后4周心室重构和心功能障碍存在时开始，用选择性ALDH 2激活剂（Alda-1）治疗心肌梗死诱导的HF大鼠6周，改善了心肌细胞缩短，基础条件下和异丙肾上腺素刺激后的心脏功能、左心室顺应性和舒张功能。重要的是，持续的Alda-1治疗显示没有毒性，并通过抑制心肌肥大和纤维化促进心脏抗重塑作用。此外，在Alda-1处理的大鼠中未观察到HF中观察到的4-羟基壬烯醛（4-HNE）-蛋白加合物和蛋白羰基的积累，这表明增加ALDH 2的活性有助于降低衰竭心脏的心脏负荷。ALDH 2激活与线粒体功能改善相关，包括线粒体呼吸控制率升高和H2 O2释放减少。重要的是，选择性ALDH 2激活降低线粒体Ca 2+诱导的通透性转换和细胞色素释放在衰竭的心脏。结论选择性激活线粒体ALDH 2可通过降低线粒体生物能学和活性氧产生的超负荷毒性作用来改善HF预后，提示ALDH 2激活剂，如Alda-1，对治疗HF患者具有潜在的治疗价值。
Aims We previously demonstrated that pharmacological activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects the heart against acute ischaemia/reperfusion injury. Here, we determined the benefits of chronic activation of ALDH2 on the progression of heart failure (HF) using a post-myocardial infarction model.Methods and results We showed that a 6-week treatment of myocardial infarction-induced HF rats with a selective ALDH2 activator (Alda-1), starting 4 weeks after myocardial infarction at a time when ventricular remodelling and cardiac dysfunction were present, improved cardiomyocyte shortening, cardiac function, left ventricular compliance and diastolic function under basal conditions, and after isoproterenol stimulation. Importantly, sustained Alda-1 treatment showed no toxicity and promoted a cardiac anti-remodelling effect by suppressing myocardial hypertrophy and fibrosis. Moreover, accumulation of 4-hydroxynonenal (4-HNE)-protein adducts and protein carbonyls seen in HF was not observed in Alda-1-treated rats, suggesting that increasing the activity of ALDH2 contributes to the reduction of aldehydic load in failing hearts. ALDH2 activation was associated with improved mitochondrial function, including elevated mitochondrial respiratory control ratios and reduced H2O2 release. Importantly, selective ALDH2 activation decreased mitochondrial Ca2+-induced permeability transition and cytochromec release in failing hearts. Further supporting a mitochondrial mechanism for ALDH2, Alda-1 treatment preserved mitochondrial function upon in vitro aldehydic load.Conclusions Selective activation of mitochondrial ALDH2 is sufficient to improve the HF outcome by reducing the toxic effects of aldehydic overload on mitochondrial bioenergetics and reactive oxygen species generation, suggesting that ALDH2 activators, such as Alda-1, have a potential therapeutic value for treating HF patients.