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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-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 adult cardiomyocytes, but not female, 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 ATP, increased oxidative stress, suppressed coenzyme Q levels, and hemoprotein dysregulation. Lastly, 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 African Americans with HF with reduced ejection fraction (HFrEF). Together, these studies reveal a crucial role for CYB5R3 in cardiomyocyte redox biology and identify a new genetic biomarker for individuals in the African American population that may potentially increase the risk of death from HFrEF.

ORGANISM(S): Mus musculus

PROVIDER: GSE206121 | GEO | 2023/06/14

REPOSITORIES: GEO

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Project description:Sudden cardiac death (SCD) associated with heart failure (HF) is a multifactorial problem requiring a systems level approach applied to suitable experimental animal models with features of the human disease. Here we examine key regulatory pathways underlying the transition from compensated hypertrophy (HYP) to decompensated HF and SCD by integrated analysis of the transcriptome, proteome and metabolome. In a guinea pig model of acquired long QT syndrome and HF/SCD, relative protein abundances from sham-operated, HYP and HF hearts were assessed using isobaric tags for relative and absolute quantification (iTRAQ), prior to liquid chromatography and tandem mass spectrometry (LC-MS/MS). Metabolites were quantified by LC-MS/MS or gas chromatography coupled to MS (GC-MS). Transcriptome profiles were obtained using DNA microarrays. The guinea pig HF proteome exhibited classic biosignatures of cardiac HYP, left ventricular dysfunction, fibrosis, cellular degeneration, inflammation and extravasation. Fatty acid metabolism, mitochondrial transcription/translation factors, antioxidant enzymes, and other mitochondrial processes, were downregulated in HF, but not HYP. Proteins upregulated in HF are consistent with extracellular matrix remodeling, cytoskeletal remodeling, and acute phase inflammation markers. Among metabolites, downregulation of acyl-carnitines was observed in HYP, while fatty acids accumulated in HF. Levels of the tricarboxylic acid (TCA) cycle metabolite, citrate, and the potent inhibitor, 2-methylcitrate, increased upon transition from HYP to HF. Correlation of the magnitude of transcript and protein changes in HF is weak (R2=0.23), indicating that targeting transcript/proteome may reveal inform post-transcriptional gene regulation in HF. Proteome/Metabolome integration suggests metabolic bottlenecks in fatty acyl-CoA processing by carnitine palmitoyl transferase (CPT1B) as well as TCA cycle inhibition. We present a model in which hallmarks of acute signaling in HF, including Ca2+ dysregulation and low cAMP levels, are coupled to mitochondrial metabolic and antioxidant defects, through a CREB/PGC1-alpha transcriptional axis.

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

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