ArticleThe Journal of clinical investigation2022
Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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The trial behind it
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Who cites it
13 citing papers in PubMed, 18 citations in OpenAlex.
- Cytochrome bBiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2026Article
- Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischaemia-reperfusion injury.Cardiovascular research · 2026Article
- A systems genetics approach to uncover mitochondrial drivers of heart failure reveals mitochondria-nuclear cross talk in genetically diverse mouse strains.bioRxiv : the preprint server for biology · 2025Article
- Endothelial CYB5R3 couples store-operated calcium entry to TRPV2 activation and vascular fitness.bioRxiv : the preprint server for biology · 2025Article
- Article
- Medium from human iPSC-derived primitive macrophages promotes adult cardiomyocyte proliferation and cardiac regeneration.Nature communications · 2025Article
- Sex-dependent adaptations in heart mitochondria from transgenic mice overexpressing cytochrome bMitochondrion · 2025Article
- The Emerging Scenario of Ferroptosis in Pancreatic Cancer Tumorigenesis and Treatment.International journal of molecular sciences · 2024Review
- CYB5R3 T117S tempers fetal hemoglobin induction by hydroxyurea in patients with sickle cell disease.Blood advances · 2024Article
- CYB5R3 T117S Genetic Mutation Is Associated With Major Adverse Cardiovascular and Cerebrovascular Events in Black Adults.Circulation. Genomic and precision medicine · 2024Article
- Vitamin E/Coenzyme Q-Dependent "Free Radical Reductases": Redox Regulators in Ferroptosis.Antioxidants & redox signaling · 2024Review
- Article
- Molecular Dynamic Simulation Analysis of a Novel Missense Variant inMedicina (Kaunas, Lithuania) · 2023Article
Corrections and comments
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Authors and funding
23 authors at 4 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
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