Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death
Nolan T. Carew, … , Guy Salama, Adam C. Straub
Nolan T. Carew, … , Guy Salama, Adam C. Straub
Published September 15, 2022
Citation Information: J Clin Invest. 2022;132(18):e147120. https://doi.org/10.1172/JCI147120.
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Research Article Cardiology

Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death

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.

Authors

Nolan T. Carew, Heidi M. Schmidt, Shuai Yuan, Joseph C. Galley, Robert Hall, Helene M. Altmann, Scott A. Hahn, Megan P. Miller, Katherine C. Wood, Bethann Gabris, Margaret C. Stapleton, Sean Hartwick, Marco Fazzari, Yijen L. Wu, Mohamed Trebak, Brett A. Kaufman, Charles F. McTiernan, Francisco J. Schopfer, Placido Navas, Patrick H. Thibodeau, Dennis M. McNamara, Guy Salama, Adam C. Straub

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Figure 1

Loss of cardiomyocyte CYB5R3 causes hypertrophy and SCD.

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Loss of cardiomyocyte CYB5R3 causes hypertrophy and SCD. (A) Detailed sc...
(A) Detailed schematic showing generation of CYB5R3-KO mice. (B) RT-qPCR and (C) Western blot analysis of total heart tissue from ac-WT and ac-CYB5R3–KO mice 5 days after tamoxifen injection (n = 5–7). (D) Survival curve comparing ac-WT (n = 8) and ac-CYB5R3–KO mice (n = 20). Day 0 represents the first day after tamoxifen injection. (E) Gross images (top) and H&E-stained hearts from ac-WT and ac-CYB5R3–KO mice 5 days after tamoxifen injection. Scale bar: 2 mm. (F) Heart weight–to–body weight ratio (n = 11), (G) wet lung weight–to–body weight (n = 3–5), (H) LV area (n = 4–6), and (I) myocyte diameter (n = 4–6) in ac-WT versus ac-CYB5R3–KO mice. Data are represented as SEM. P values were calculated by Student’s t test.