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  • Ovid Technologies (Wolters Kluwer Health)  (2)
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  • 1
    Online Resource
    Online Resource
    Abstract 15696: Cytochrome B5 Reductase 3 Sensitizes Soluble Guanylate Cyclase to Nitric Oxide
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Circulation Vol. 132, No. suppl_3 ( 2015-11-10)
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    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 132, No. suppl_3 ( 2015-11-10)
    Abstract: Impaired soluble guanylyl cyclase (sGC)-dependent nitric oxide (NO) signaling has been linked to numerous cardiovascular diseases (CVD) such as hypertension, myocardial infarction and atherosclerosis. Despite emerging evidence indicating the importance of sGC function within the cardiovascular system, the basic mechanisms that regulate sGC activity remain incompletely understood. Herein, we provide in vitro and in vivo evidence that cytochrome b5 reductase 3 (Cyb5R3) is an sGC heme iron reductase and regulates downstream cGMP signaling. Of major significance, we also demonstrate that a Cyb5R3 T116S polymorphism with allele frequency of 0.23 in African Americans associates with increase blood pressure and is incapable of reducing sGC. Proximity ligation assay (PLA) experiments show that endogenous Cyb5R3 and oxidized sGC associate. Knockdown of Cyb5R3 results in reduced cGMP production and downstream signaling in rat aortic smooth muscle cells (SMC). Overexpression of Cyb5R3 not only rescues cGMP production but also increases baseline cGMP, whereas T116S mutant does not. Finally, inhibition of Cyb5R3 in mice significantly increases systemic blood pressure. Our studies are the first to identify an sGC heme iron reductase, provide evidence for Cyb5R3 as a key biological regulator of sGC activity and vascular tone in SMC, and link a human polymorphism of Cyb5R3 to increased blood pressure; all of which may lead to the development of novel therapeutics targeting Cyb5R3 for the treatment of CVD. Importantly, the co-expression of Cyb5R3 and sGC in multiple cells types suggests that this regulation of sGC activity may have broad applications for multiple physiological and pathophysiological processes. Results: Conclusions:
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.132.suppl_3.15696
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1466401-X
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  • 2
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    Online Resource
    Abstract 107: Cytochrome B5 Reductase 3 Sensitizes Soluble Guanylate Cyclase to Nitric Oxide in Vascular Smooth Muscle
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Hypertension Vol. 66, No. suppl_1 ( 2015-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 66, No. suppl_1 ( 2015-09)
    Abstract: The inability nitric oxide (NO) to stimulate soluble guanylate cyclase (sGC) has been linked to numerous cardiovascular diseases (CVD) including hypertension. While several studies have defined the importance of sGC expression in the cardiovascular system, the basic mechanisms that regulate sGC activity remain incompletely understood. Here, we report for the first time that sGC heme iron redox state, which is essential for NO-induced sGC activation, is regulated by cytochrome B5 reductase 3 (CyB5R3). Genetic knockdown and pharmacological inhibition of CyB5R3 in primary rat vascular smooth muscle cells resulted in a 60% loss in cGMP production. Conversely, the sGC activator Bay 58-2667, which activates oxidized or heme free sGC, reversed these effects. Consistent with our cell culture work, purified protein studies demonstrate that CyB5R3 can directly reduce oxidized sGC heme iron and sensitize sGC to NO. To test the functional importance of Cyb5R3 activity, we cultured mouse thoracodorsal arteries with a pharmacological inhibitor of Cyb5R3 (ZINC 747) and performed vascular reactivity studies using pressure myography. Arteries treated with ZINC 747 showed decreased responsiveness the NO donor DETA-NONOate but increase sensitivity to Bay 58-2667. We then treated mice with 10mg/kg/day of ZINC 747 using osmotic mini pumps, which caused an increase in mean arterial blood pressure (107.5±3.4 vs 131±13.16) measured via radio telemetry. Lastly, translational studies reveal that the CyB5R3 T116S polymorphism with allele frequency 0.23 only in African Americans is unable to reduce sGC and correlates with increased blood pressure. Considering the defining role of sGC in NO signaling and the fact that the oxidation state of sGC may predict responses to NO therapies and new classes of sGC activator medications, we anticipate that these studies may significantly impact our understanding of biology, precision therapeutics (right drug for the right patient) and pharmacogenetics (T117S SNP based drug selection).
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.66.suppl_1.107
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 2094210-2
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