The pathogenesis of essential hypertension is multifactorial and the etiology, in a vast majority of cases, remains unknown. To date, both clinical and experimental evidence concludes that reduced NO bioavailability and/or responsiveness is a contributing factor in the pathogenesis of HTN. We previously demonstrated that cytochrome B5 reductase 3 (Cyb5R3) controls NO diffusion from endothelium to vascular smooth muscle cells (VSMC) by regulation of endothelial alpha globin heme iron redox state. We have now identified an additional heme protein regulated by Cyb5R3 in VSMC: soluble guanylyl cyclase (sGC), the NO receptor. Preliminary data demonstrates that cytochorome b5 reductase 3 (Cyb5R3) regulates sGC function, NO signal transduction, cyclic guanosine monophosphate (cGMP) levels, arterial tone and blood pressure by regulating sGC heme iron redox state. Our overarching hypothesis states that Cyb5R3 regulates sGC redox state and activity to control arterial vascular tone and blood pressure. We will test this hypothesis using three specific aims:
Aim 1 will define the molecular mechanisms by which Cyb5R3 controls sGC heme reduction, Aim 2 will determine the regulatory role of VSMC Cyb5R3 in cGMP signaling and Aim 3 will define the role of SMC Cyb5R3 function in vascular reactivity and blood pressure control. Considering the defining role of sGC in NO signaling and the fact that the oxidation state of sGC may predict responses to new classes of sGC activator and stimulator medications, we anticipate that these studies may significantly impact our understanding of biology, precision therapeutics (right drug for the right patient) and pharmacogenetics (polymorphism based drug selection).
In the United States, approximately 77.9 million adults have systemic hypertension (HTN), a significant risk factor for cardiovascular disease. A vast amount of clinical and experimental evidence has concluded that dysfunctional nitric oxide (NO) signaling, leading to increased vasoconstriction, is a common pathogenic feature of HTN. This proposal seeks to advance biology and medicine by focusing on cytochrome b5 reductase 3 (Cyb5R3) and its role in regulating the nitric oxide receptor, soluble guanylate cyclase. We anticipate that these studies may impact our understanding of biology, precision therapeutics (right drug for the right patient) and pharmacogenetics (polymorphism based drug selection).
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