Metabolic Remodeling Induced by Mitochondrial Aldehyde Stress Stimulates Tolerance to Oxidative Stress in the Heart
Metabolic Remodeling Induced by Mitochondrial Aldehyde Stress Stimulates Tolerance to Oxidative Stress in the Heart
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DOI：
10.1161/circresaha.109.206607
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发表时间：
2009-11-20
影响因子：
20.1
通讯作者：
Fukuda, Keiichi
中科院分区：
文献类型：
--
作者：
Endo, Jin;Sano, Motoaki;Fukuda, Keiichi
目的：我们研究了心脏如何补偿醛的加速积累。方法和结果：醛脱氢酶2(ALDH2)在醛的主要来源--线粒体中的醛解毒中起主要作用。建立了携带ALDH2基因的单核苷酸多态(ALDH2*2)转基因小鼠。这种多态具有显性-负性效应，TG小鼠对广泛的醛表现出ALDH活性受损。尽管线粒体基质向氧化状态转变，但超声心动图显示ALDH2*2 TG心脏的左心功能正常，并且由于代谢重塑，对缺血/再灌注损伤诱导的氧化应激具有意外的耐受性。线粒体醛应激刺激真核细胞翻译起始因子2α磷酸化。随后激活转录因子-4的翻译和转录激活促进了参与氨基酸生物合成和运输的酶的表达，最终为谷胱甘肽的生物合成提供了前体氨基酸。ALDH2*2 TG组大鼠心肌细胞内谷胱甘肽水平是野生型对照组的1.37倍。ATF4杂合敲除可钝化ALDH2*2甘油三酯心脏细胞内谷胱甘肽水平的增加，从而减弱氧化应激抵抗表型。此外，在ALDH2*2 TG心脏中，通过戊糖磷酸途径的糖酵解和NADPH的产生被激活。(氧化谷胱甘肽的循环需要NADPH。)结论：本研究结果表明，心肌线粒体醛应激诱导代谢重塑，导致谷胱甘肽-氧化还原循环的激活，从而对缺血/再灌流诱导的急性氧化应激具有抵抗作用。(中国保监会决议2009；105：1118-1127。)
Rationale: Aldehyde accumulation is regarded as a pathognomonic feature of oxidative stress-associated cardiovascular disease.Objective: We investigated how the heart compensates for the accelerated accumulation of aldehydes.Methods and Results: Aldehyde dehydrogenase 2 (ALDH2) has a major role in aldehyde detoxification in the mitochondria, a major source of aldehydes. Transgenic (Tg) mice carrying an Aldh2 gene with a single nucleotide polymorphism (Aldh2*2) were developed. This polymorphism has a dominant-negative effect and the Tg mice exhibited impaired ALDH activity against a broad range of aldehydes. Despite a shift toward the oxidative state in mitochondrial matrices, Aldh2*2 Tg hearts displayed normal left ventricular function by echocardiography and, because of metabolic remodeling, an unexpected tolerance to oxidative stress induced by ischemia/reperfusion injury. Mitochondrial aldehyde stress stimulated eukaryotic translation initiation factor 2 alpha phosphorylation. Subsequent translational and transcriptional activation of activating transcription factor-4 promoted the expression of enzymes involved in amino acid biosynthesis and transport, ultimately providing precursor amino acids for glutathione biosynthesis. Intracellular glutathione levels were increased 1.37-fold in Aldh2*2 Tg hearts compared with wild-type controls. Heterozygous knockout of Atf4 blunted the increase in intracellular glutathione levels in Aldh2*2 Tg hearts, thereby attenuating the oxidative stress-resistant phenotype. Furthermore, glycolysis and NADPH generation via the pentose phosphate pathway were activated in Aldh2*2 Tg hearts. (NADPH is required for the recycling of oxidized glutathione.)Conclusions: The findings of the present study indicate that mitochondrial aldehyde stress in the heart induces metabolic remodeling, leading to activation of the glutathione-redox cycle, which confers resistance against acute oxidative stress induced by ischemia/reperfusion. (Circ Res. 2009; 105: 1118-1127.)