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.

CYB5R3 T117S Genetic Mutation Is Associated With Major Adverse Cardiovascular and Cerebrovascular Events in Black Adults

“…4 Our results align with previous research, indicating Black patients with congestive heart failure with the CYB5R3 T117S genotype had a 20% reduction in survival compared with White patients. 2 In this study, CYB5R3 T117S genotype correlated with a higher atherothrombotic events after adjusting for comorbidities. This finding supports previous studies reporting higher ischemic event rates in Black women with prothrombotic phenotypes.…”

“…A high prevalence of genetic polymorphisms with partial loss-of-function of CYB5R3 (cytochrome B5 reductase 3) termed T117S has been reported in Black but not White people. 1 CYB5R3 plays a significant role in cardiac myocyte redox signaling 2 and has been associated with congestive heart failure and arrhythmias in Black adults. 2 In this study, we investigated whether CYB5R3 T117S genotype is associated with major adverse cardiovascular and cerebrovascular events (MACCEs) in Black adults enrolled in HeartSCORE (Heart Strategies Concentrating on Risk Evaluation) study.…”

Molecular Dynamic Simulation Analysis of a Novel Missense Variant in CYB5R3 Gene in Patients with Methemoglobinemia

“…An important substrate of the CYB5R3 protein is CYBR, which plays a crucial role in the electron-transfer reactions performed by CYB5R3. CYB5 is a heme-containing protein expressed in animals, plants and fungi that acts as an electron transporter in a variety of important reactions [ 36 , 37 ]. Each heme group has iron in the reduced (Fe +2 ) state.…”

Cytochrome b5 reductases: Redox regulators of cell homeostasis

“…( 100 ) demonstrated that the cardiomyocyte-specific deletion of CYB5R3 in male mice causes cardiac hypertrophy and sudden cardiac death. These phenotypic differences are accompanied by elevated oxidative stress, decreased CoQ levels, and hemoprotein dysregulation in mouse CYB5R3-cardiomyocyte–specific knockout hearts ( 100 ). From a translational point of view, Carew et al.…”

“…From a translational point of view, Carew et al. ( 100 ) revealed that a high-frequency missense genetic variant of CYB5R3, T117S, is associated with decreased event-free survival in those with African ancestry suffering from heart failure with reduced ejection fraction. It was shown that the membrane-bound T117S variant exhibits 50% reduced enzymatic activity when compared to WT CYB5R3.…”