Mitochondrial aldehyde dehydrogenase 2 plays protective roles in heart failure after myocardial infarction via suppression of the cytosolic JNK/p53 pathway in mice.
Mitochondrial aldehyde dehydrogenase 2 plays protective roles in heart failure after myocardial infarction via suppression of the cytosolic JNK/p53 pathway in mice.
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DOI：
10.1161/jaha.113.000779
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发表时间：
2014-09-18
影响因子：
5.4
通讯作者：
Ge J
中科院分区：
文献类型：
--
作者：
Sun A;Zou Y;Wang P;Xu D;Gong H;Wang S;Qin Y;Zhang P;Chen Y;Harada M;Isse T;Kawamoto T;Fan H;Yang P;Akazawa H;Nagai T;Takano H;Ping P;Komuro I;Ge J
越来越多的证据表明，线粒体醛脱氢酶2 （ALDH2）在心脏损伤保护中的关键作用；然而，这种酶的下游胞质作用在很大程度上是不确定的。蛋白质组学分析发现心肌梗死后大鼠心力衰竭模型心脏中线粒体ALDH2显著下调。通过过度表达ALDH2或其突变体或消融ALDH2基因（ALDH2敲除）的小鼠模型和ALDH2表达和活性改变的新生儿心肌细胞，阐明了ALDH2作用的机制。在ALDH2基因敲除或ALDH2基因突变过表达的小鼠中，心肌梗死后左心室扩张、功能障碍和心肌细胞死亡加剧，而在ALDH2基因过表达的小鼠中，这一现象明显减弱。利用ALDH2活性缺乏的心肌细胞缺氧模型，我们观察到心肌细胞明显凋亡，活性醛- 4 -羟基- 2 -壬烯醛（4 - HNE）的积累增加。我们随后研究了线粒体ALDH2和4‐HNE对相关细胞质保护途径的影响。我们的数据表明，通过JNK的磷酸化，4‐HNE‐刺激p53上调，伴随着心肌细胞凋亡的增加，而抑制p53可减轻心肌细胞凋亡。重要的是，4 - HNE的升高也引发了胞质HSP70的降低，进一步证实了4 - HNE由线粒体ALDH2的下调所引发的胞质作用。线粒体中ALDH2的下调诱导4 - HNE的升高，通过随后抑制HSP70、JNK的磷酸化和p53的激活导致心肌细胞凋亡。这一连串的分子事件发生在线粒体和细胞质中，导致了心力衰竭的机制。
Increasing evidence suggests a critical role for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in protection against cardiac injuries; however, the downstream cytosolic actions of this enzyme are largely undefined. Proteomic analysis identified a significant downregulation of mitochondrial ALDH2 in the heart of a rat heart failure model after myocardial infarction. The mechanistic insights underlying ALDH2 action were elucidated using murine models overexpressing ALDH2 or its mutant or with the ablation of the ALDH2 gene (ALDH2 knockout) and neonatal cardiomyocytes undergoing altered expression and activity of ALDH2. Left ventricle dilation and dysfunction and cardiomyocyte death after myocardial infarction were exacerbated in ALDH2‐knockout or ALDH2 mutant‐overexpressing mice but were significantly attenuated in ALDH2‐overexpressing mice. Using an anoxia model of cardiomyocytes with deficiency in ALDH2 activities, we observed prominent cardiomyocyte apoptosis and increased accumulation of the reactive aldehyde 4‐hydroxy‐2‐nonenal (4‐HNE). We subsequently examined the impacts of mitochondrial ALDH2 and 4‐HNE on the relevant cytosolic protective pathways. Our data documented 4‐HNE‐stimulated p53 upregulation via the phosphorylation of JNK, accompanying increased cardiomyocyte apoptosis that was attenuated by inhibition of p53. Importantly, elevation of 4‐HNE also triggered a reduction of the cytosolic HSP70, further corroborating cytosolic action of the 4‐HNE instigated by downregulation of mitochondrial ALDH2. Downregulation of ALDH2 in the mitochondria induced an elevation of 4‐HNE, leading to cardiomyocyte apoptosis by subsequent inhibition of HSP70, phosphorylation of JNK, and activation of p53. This chain of molecular events took place in both the mitochondria and the cytosol, contributing to the mechanism underlying heart failure.