Abstract 575: Loss of Function Variant in CYB5R3 Associates With Exacerbated Cardiac Hypertrophy in Mice
Circulation Research(2019)
摘要
African Americans (AA) are 20 times more likely to be diagnosed with heart failure (HF) before the age of 50 and 2 times more likely to die from heart failure. Previous reports have shown AA with HF have diminished nitric oxide (NO) signaling, a pathway critical for cardiac contractility. NO signals, in part, via binding reduced heme iron (Fe 2+ ) in soluble guanylyl cyclase (sGC) leading to cyclic guanosine monophosphate (cGMP) generation. Recently, our lab reported that cytochrome b5 reductase 3 (Cyb5R3) reduces oxidized sGC heme-iron from the oxidized (Fe 3+ ) to the reduced (Fe 2+ ) state, thereby sensitizing sGC to NO. However, the role of Cyb5R3 in the setting of HF remains elusive. It is known that a high frequency Cyb5R3 T117S single nucleotide polymorphism (23% minor allele frequency) exists and is enriched in individuals with African ancestry. To determine the impact of T117S in HF outcomes, we completed a retrospective study from AHEFT and GRACE trials. Our data show that Cyb5R3 T117S carriers have significantly accelerated time to death/transplant. Additionally, biobank HF samples from AA samples show an enrichment of Cyb5R3 T117S carriers from 0.23 to 0.4. To assess the impact of Cyb5R3 T117S on sGC/cGMP signaling in the heart, ventricular cGMP levels in AA with HF were examined. Pooled Cyb5R3 T117S carriers have significantly decreased cGMP relative to non-carriers. Next, we determined if this variant impacts sGC heme redox state. Using purified protein activity assays, we found that Cyb5R3 T117S results in a 60% loss-of-function and an inability to reduce oxidized sGC. Lastly, to test the in vivo impact of the Cyb5R3 T117S variant in heart failure, we generated a novel Cyb5R3 T117S mouse. Transverse aortic constriction (TAC) studies in Cyb5R3 T117S mice show significantly accelerates cardiac hypertrophy relative to wild-type TAC controls. Taken together, these data suggest Cyb5R3 T117S may be a disease modifying variant that augments hypertrophic signaling through an sGC-dependent mechanism.
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关键词
exacerbated cardiac hypertrophy,cyb5r3 associates
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