Smooth muscle cell CYB5R3 preserves cardiac and vascular function under chronic hypoxic stress

Durgin, Brittany G; Wood, Katherine C.; Hahn, Scott; McMahon, Brendan; Baust, Jeffrey; Straub, Adam C.

doi:10.1016/j.yjmcc.2021.09.005

Cited by 12 publications

(7 citation statements)

References 49 publications

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“…The CYB5R3 T117S genotype has ≈50% reduced enzyme activity compared with normal CYB5R3. 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.…”

supporting

confidence: 91%

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

Chaudhary,

Straub,

Aggor

et al. 2024

Circ: Genomic and Precision Medicine

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supporting

confidence: 91%

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

Chaudhary,

Straub,

Aggor

et al. 2024

Circ: Genomic and Precision Medicine

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“…Although there is evidence that CYB5R3 plays an important role in maintaining cell homeostasis in aging and disease ( 16 , 18 – 20 , 29 , 30 ), very little is known about the function of CYB5R3 in the context of lung physiology and response to injury. Here we showed that deficiency of CYBR3 in AECIIs led to the prolonged activation of the pro-fibrotic factor TGF-β1 and increased susceptibility to lung fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Cytochrome b5 reductase 3 (CYB5R3) is a membrane bound reductase that utilizes NADH as substrate and participates in reduction of several key redox molecules (12)(13)(14). Recently, we showed that in smooth muscle cell CYB5R3 can directly reduce oxidized heme in soluble guanylate cyclase (sGC) which is required for nitric oxide (NO)stimulated 3'5' cyclic guanosine monophosphate (cGMP) production (12,(15)(16)(17). While there is growing evidence for a critical role for CYB5R3 in the cardiovascular system and in aging (18)(19)(20), very little is known about the function of CYB5R3 in the context of physiological lung homeostasis and pathology, more specifically during fibrosis.…”

Section: Introductionmentioning

confidence: 99%

CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling

et al. 2023

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Type II alveolar epithelial cell (AECII) redox imbalance contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF) -a deadly disease with restricted and limited treatment options. Here, we show that expression of membrane-bound cytochrome B5 reductase 3 (CYB5R3), an enzyme critical for maintaining cellular redox homeostasis and soluble guanylate cyclase (sGC) heme iron redox state, is diminished in IPF AECII. Deficiency of CYB5R3 in AECII leads to sustained activation of the profibrotic factor TGF-β1 and increased susceptibility to lung fibrosis. We further show that CYB5R3 is a critical regulator of ERK1/2 phosphorylation and sGC-cGMP-protein kinase G axis that modulates activation of TGF-β1 signaling pathway. We demonstrate that sGC agonists are effective in reducing the pulmonary fibrotic outcomes of in vivo deficiency of CYB5R3 in AECII. Taken together, these results establish that CYB5R3 in AECII is required to maintain resilience against lung injury and fibrosis, and that therapeutic manipulation of sGC redox state could provide a basis for treating fibrotic conditions in the lung and beyond.

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“…We recently showed that CYB5R3 regulates the heme redox state of hemoglobin α in small artery and arteriolar endothelial cells, controlling NO diffusion to VSMCs ( 14 ). Additionally, we uncovered that CYB5R3 sensitizes sGC to NO by reducing sGC heme iron, functioning as a control mechanism for intracellular cGMP levels in VSMCs ( 27 , 28 , 53 ). While these reports show that CYB5R3 modulates oxidative stress, mitochondrial function, CoQ redox regulation, and NO/cGMP signaling in a diverse number of cell types, the data provided herein support a central role for CYB5R3 as a “redox hub” in cardiomyocytes, governing independent redox signaling pathways in a unified manner.…”

Section: Discussionmentioning

confidence: 99%

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

Carew¹,

Schmidt²,

Yuan³

et al. 2022

Journal of Clinical Investigation

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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.

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Smooth muscle cell CYB5R3 preserves cardiac and vascular function under chronic hypoxic stress

Cited by 12 publications

References 49 publications

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

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

CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling

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

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