title: Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart.
abstract: BACKGROUND
  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.
  
  
  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 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.
authors.affiliation: Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Endo
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.forename: Takaharu
authors.initials: T
authors.lastname: Katayama
authors.forename: Takako
authors.initials: T
authors.lastname: Hishiki
authors.forename: Ken
authors.initials: K
authors.lastname: Shinmura
authors.forename: Shintaro
authors.initials: S
authors.lastname: Morizane
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuhashi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katsumata
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ito
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nagahata
authors.forename: Satori
authors.initials: S
authors.lastname: Marchitti
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nishimaki
authors.forename: Alexander Martin
authors.initials: AM
authors.lastname: Wolf
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Hattori
authors.forename: Vasilis
authors.initials: V
authors.lastname: Vasiliou
authors.forename: Takeshi
authors.initials: T
authors.lastname: Adachi
authors.forename: Ikuroh
authors.initials: I
authors.lastname: Ohsawa
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirabayashi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohta
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000222:Adaptation, Physiological / Q000502:physiology; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004452:Echocardiography; D004789:Enzyme Activation / Q000502:physiology; D004790:Enzyme Induction / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D055442:Metabolome / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000502:physiology*; D010427:Pentose Phosphate Pathway / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D000447:Aldehydes; C081452:Atf4 protein, mouse; D051701:Activating Transcription Factor 4; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005978:Glutathione; D005947:Glucose