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Tytuł:
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Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death.
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Autorzy:
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Carew NT; Heart, Lung, Blood and Vascular Medicine Institute.; Department of Pharmacology and Chemical Biology.
Schmidt HM; Heart, Lung, Blood and Vascular Medicine Institute.; Department of Pharmacology and Chemical Biology.
Yuan S; Heart, Lung, Blood and Vascular Medicine Institute.
Galley JC; Heart, Lung, Blood and Vascular Medicine Institute.; Department of Pharmacology and Chemical Biology.
Hall R; Heart, Lung, Blood and Vascular Medicine Institute.; Department of Pharmacology and Chemical Biology.
Altmann HM; Heart, Lung, Blood and Vascular Medicine Institute.
Hahn SA; Heart, Lung, Blood and Vascular Medicine Institute.
Miller MP; Heart, Lung, Blood and Vascular Medicine Institute.
Wood KC; Heart, Lung, Blood and Vascular Medicine Institute.; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and.
Gabris B; Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Stapleton MC; Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Hartwick S; Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Fazzari M; Department of Pharmacology and Chemical Biology.
Wu YL; Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Trebak M; Heart, Lung, Blood and Vascular Medicine Institute.; Department of Pharmacology and Chemical Biology.
Kaufman BA; Heart, Lung, Blood and Vascular Medicine Institute.; Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
McTiernan CF; Heart, Lung, Blood and Vascular Medicine Institute.; Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Schopfer FJ; Heart, Lung, Blood and Vascular Medicine Institute.; Department of Pharmacology and Chemical Biology.
Navas P; Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.
Thibodeau PH; Department of Microbiology and Molecular Genetics and.
McNamara DM; Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Salama G; Heart, Lung, Blood and Vascular Medicine Institute.; Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Straub AC; Heart, Lung, Blood and Vascular Medicine Institute.; Department of Pharmacology and Chemical Biology.; Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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Źródło:
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The Journal of clinical investigation [J Clin Invest] 2022 Sep 15; Vol. 132 (18). Date of Electronic Publication: 2022 Sep 15.
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Typ publikacji:
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Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
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Język:
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English
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Imprint Name(s):
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Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
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MeSH Terms:
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Heart Failure*/genetics
Heart Failure*/metabolism
Myocytes, Cardiac*/metabolism
Animals ; Death, Sudden, Cardiac ; Male ; Mice ; Mice, Knockout ; Oxidation-Reduction ; Stroke Volume
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Grant Information:
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R21 NS112787 United States NS NINDS NIH HHS; R01 DK112854 United States DK NIDDK NIH HHS; R21 EB023507 United States EB NIBIB NIH HHS; R21 NS121706 United States NS NINDS NIH HHS; R01 GM125944 United States GM NIGMS NIH HHS; R01 HL133864 United States HL NHLBI NIH HHS; R01 GM122091 United States GM NIGMS NIH HHS; R35 HL161177 United States HL NHLBI NIH HHS; F31 HL151173 United States HL NHLBI NIH HHS; R01 HL128304 United States HL NHLBI NIH HHS; S10 OD028483 United States OD NIH HHS; R35 HL150778 United States HL NHLBI NIH HHS; F31 HL149241 United States HL NHLBI NIH HHS
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Contributed Indexing:
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Keywords: Cardiology; Heart failure; Nitric oxide; Radicals
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Entry Date(s):
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Date Created: 20220915 Date Completed: 20220916 Latest Revision: 20230920
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Update Code:
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20240105
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PubMed Central ID:
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PMC9479700
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DOI:
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10.1172/JCI147120
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PMID:
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36106636
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Sudden cardiac death (SCD) in patients with heart failure (HF) is allied with an imbalance in reduction and oxidation (redox) signaling in cardiomyocytes; however, the basic pathways and mechanisms governing redox homeostasis in cardiomyocytes are not fully understood. Here, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to regulate redox signaling in erythrocytes and vascular cells, is essential for cardiomyocyte function. Using a conditional cardiomyocyte-specific CYB5R3-knockout mouse, we discovered that deletion of CYB5R3 in male, but not female, adult cardiomyocytes causes cardiac hypertrophy, bradycardia, and SCD. The increase in SCD in CYB5R3-KO mice is associated with calcium mishandling, ventricular fibrillation, and cardiomyocyte hypertrophy. Molecular studies reveal that CYB5R3-KO hearts display decreased adenosine triphosphate (ATP), increased oxidative stress, suppressed coenzyme Q levels, and hemoprotein dysregulation. Finally, from a translational perspective, we reveal that the high-frequency missense genetic variant rs1800457, which translates into a CYB5R3 T117S partial loss-of-function protein, associates with decreased event-free survival (~20%) in Black persons with HF with reduced ejection fraction (HFrEF). Together, these studies reveal a crucial role for CYB5R3 in cardiomyocyte redox biology and identify a genetic biomarker for persons of African ancestry that may potentially increase the risk of death from HFrEF.