Published online before print October 8, 2009, doi: 10.1161/CIRCRESAHA.109.206607
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Submitted on June 19, 2009
Revised on September 25, 2009
Accepted on September 29, 2009
Metabolic Remodeling Induced by Mitochondrial Aldehyde Stress Stimulates Tolerance to Oxidative Stress in the Heart
Jin Endo ;
From the Department of Regenerative Medicine and Advanced Cardiac Therapeutics (J.E., M. Sano, T.K., S. Morizane, T.M., Y.K., Y.Z., H.I., F.H., K.F.); Cardiology Division (J.E., T.K., T.M., Y.K., S. Ogawa), Department of Internal Medicine; Department of Biochemistry and Integrative Medical Biology (T.H., Y.N., T.A., M. Suematsu); and Division of Geriatric Medicine (K.S.), Keio University School of Medicine, Tokyo, Japan; Precursory Research for Embryonic Science and Technology (PRESTO) (M. Sano), Japan Science and Technology Agency, Saitama, Japan; Department of Biochemistry and Cell Biology (K.N., A.M.W., I.O., S. Ohta), Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, Kawasaki, Japan; Department of Pharmaceutical Sciences (S. Marchitti, V.V.), University of Colorado Health Sciences Center, Denver; Department of Metabolome (H.N., R.T.), University of Tokyo, Japan; and Neuronal Circuit Mechanisms Research Group (Y.H.), Brain Science Institute, RIKEN, Saitama, Japan.
* To whom correspondence should be addressed. E-mail: msano{at}sc.itc.keio.ac.jp.
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
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.
Key words: cardiac metabolism • oxidative stress • aldehyde • stress response
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  B. G. Hill and A. Bhatnagar Beyond Reactive Oxygen Species: Aldehydes as Arbitrators of Alarm and Adaptation Circ. Res., November 20, 2009; 105(11): 1044 - 1046. [Full Text] [PDF]
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