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 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.
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 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: Vikas Kumar; Timothy Dean Calamaras; Dagmar Haeussler; Wilson Steven Colucci; Richard Alan Cohen; Mark Errol McComb; David Pimentel; Markus Michael Bachschmid Journal: Antioxid Redox Signal Date: 2012-08-10 Impact factor: 8.401
Authors: Shahid P Baba; Deqing Zhang; Mahavir Singh; Sujith Dassanayaka; Zhengzhi Xie; Ganapathy Jagatheesan; Jingjing Zhao; Virginia K Schmidtke; Kenneth R Brittian; Michael L Merchant; Daniel J Conklin; Steven P Jones; Aruni Bhatnagar Journal: J Mol Cell Cardiol Date: 2018-04-05 Impact factor: 5.000
Authors: Shengfang Jin; Jiang Chen; Lizao Chen; Gavin Histen; Zhizhong Lin; Stefan Gross; Jeffrey Hixon; Yue Chen; Charles Kung; Yiwei Chen; Yufei Fu; Yuxuan Lu; Hui Lin; Xiujun Cai; Hua Yang; Rob A Cairns; Marion Dorsch; Shinsan M Su; Scott Biller; Tak W Mak; Yong Cang Journal: Proc Natl Acad Sci U S A Date: 2015-07-06 Impact factor: 11.205
Authors: Brian C Jackson; Roger S Holmes; Donald S Backos; Philip Reigan; David C Thompson; Vasilis Vasiliou Journal: Chem Biol Interact Date: 2012-12-13 Impact factor: 5.192
Authors: Jingjing Zhao; Dheeraj Kumar Posa; Vijay Kumar; David Hoetker; Amit Kumar; Smirthy Ganesan; Daniel W Riggs; Aruni Bhatnagar; Michael F Wempe; Shahid P Baba Journal: Amino Acids Date: 2018-11-17 Impact factor: 3.520