ハットリ　フミユキ   HATTORI FUMIYUKI   服部　文幸    所属   関西医科大学  iPS・幹細胞再生医学講座    職種   研究教授
論文種別	原著(症例報告除く)
言語種別	英語
査読の有無	その他(不明)
表題	Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart.
掲載誌名	正式名：Circulation research 略　 称：Circ Res ISSNコード：1524457100097330
巻・号・頁	105(11),pp.1118-27
著者・共著者	Endo Jin, Sano Motoaki, Katayama Takaharu, Hishiki Takako, Shinmura Ken, Morizane Shintaro, Matsuhashi Tomohiro, Katsumata Yoshinori, Zhang Yan, Ito Hideyuki, Nagahata Yoshiko, Marchitti Satori, Nishimaki Kiyomi, Wolf Alexander Martin, Nakanishi Hiroki, Hattori Fumiyuki, Vasiliou Vasilis, Adachi Takeshi, Ohsawa Ikuroh, Taguchi Ryo, Hirabayashi Yoshio, Ohta Shigeo, Suematsu Makoto, Ogawa Satoshi, Fukuda Keiichi
発行年月	2009/11
概要	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 2alpha 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 bluntedthe 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.
DOI	10.1161/CIRCRESAHA.109.206607
PMID	19815821