Xiaoding Wang1, Guangyu Zhang2, Subhajit Dasgupta2, Erica L Niewold2, Chao Li2, Qinfeng Li2, Xiang Luo2, Lin Tan3, Anwarul Ferdous2, Philip L Lorenzi3, Beverly A Rothermel2,4, Thomas G Gillette2, Christopher M Adams5, Philipp E Scherer6, Joseph A Hill2,4, Zhao V Wang2. 1. Department of Cardiology, Renmin Hospital of Wuhan University, Hubei, China (X.W.). 2. Division of Cardiology, Department of Internal Medicine (X.W., G.Z., S.D., E.L.N., C.L., Q.L., X.L., A.F., B.A.R., T.G.G., J.A.H., Z.V.W.), University of Texas Southwestern Medical Center, Dallas. 3. Metabolomics Core Facility, Department of Bioinformatics & Computational Biology, University of Texas MD Anderson Cancer Center, Houston (L.T., P.L.L.). 4. Department of Molecular Biology (B.A.R., J.A.H.), University of Texas Southwestern Medical Center, Dallas. 5. Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, Minnesota (C.A.M.). 6. Touchstone Diabetes Center, Department of Internal Medicine (P.E.S.), University of Texas Southwestern Medical Center, Dallas.
Abstract
BACKGROUND: Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. METHODS: Pressure overload was triggered by transverse aortic constriction in mice. Transcriptomic and metabolomic regulations were evaluated by RNA-sequencing and metabolomics, respectively. Stable isotope tracer labeling experiments were conducted to determine metabolic flux in vitro. Neonatal rat ventricular myocytes and H9c2 cells were used to examine molecular mechanisms. RESULTS: We show that production of cardiomyocyte NADPH, a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with fibrosis and cardiomyopathy. We report that the pentose phosphate pathway and mitochondrial serine/glycine/folate metabolic signaling, 2 NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced by transverse aortic constriction. We identify ATF4 (activating transcription factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these 2 pathways. Consistently, joint pathway analysis of transcriptomic and metabolomic data reveal that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in neonatal rat ventricular myocytes increases NADPH-producing enzymes' whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression augments metabolic flux within these 2 pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of transverse aortic constriction and accelerates heart failure development, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. CONCLUSIONS: Our findings reveal that ATF4 plays a critical role in the heart under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.
BACKGROUND: Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. METHODS: Pressure overload was triggered by transverse aortic constriction in mice. Transcriptomic and metabolomic regulations were evaluated by RNA-sequencing and metabolomics, respectively. Stable isotope tracer labeling experiments were conducted to determine metabolic flux in vitro. Neonatal rat ventricular myocytes and H9c2 cells were used to examine molecular mechanisms. RESULTS: We show that production of cardiomyocyte NADPH, a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with fibrosis and cardiomyopathy. We report that the pentose phosphate pathway and mitochondrial serine/glycine/folate metabolic signaling, 2 NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced by transverse aortic constriction. We identify ATF4 (activating transcription factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these 2 pathways. Consistently, joint pathway analysis of transcriptomic and metabolomic data reveal that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in neonatal rat ventricular myocytes increases NADPH-producing enzymes' whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression augments metabolic flux within these 2 pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of transverse aortic constriction and accelerates heart failure development, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. CONCLUSIONS: Our findings reveal that ATF4 plays a critical role in the heart under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.
Authors: H A Rockman; R S Ross; A N Harris; K U Knowlton; M E Steinhelper; L J Field; J Ross; K R Chien Journal: Proc Natl Acad Sci U S A Date: 1991-09-15 Impact factor: 11.205
Authors: Davy Vanhoutte; Tobias G Schips; Alexander Vo; Kelly M Grimes; Tanya A Baldwin; Matthew J Brody; Federica Accornero; Michelle A Sargent; Jeffery D Molkentin Journal: Nat Commun Date: 2021-06-24 Impact factor: 14.919
Authors: Yuan Zhang; Paul V Taufalele; Jesse D Cochran; Isabelle Robillard-Frayne; Jonas Maximilian Marx; Jamie Soto; Adam J Rauckhorst; Fariba Tayyari; Alvin D Pewa; Lawrence R Gray; Lynn M Teesch; Patrycja Puchalska; Trevor R Funari; Rose McGlauflin; Kathy Zimmerman; William J Kutschke; Thomas Cassier; Shannon Hitchcock; Kevin Lin; Kevin M Kato; Jennifer L Stueve; Lauren Haff; Robert M Weiss; James E Cox; Jared Rutter; Eric B Taylor; Peter A Crawford; E Douglas Lewandowski; Christine Des Rosiers; E Dale Abel Journal: Nat Metab Date: 2020-10-26