Abstract P139: Cytochrome B5 Reductase 3 Biases Activation of Soluble Guanylyl Cyclase in Resistance Arteries

Abstract

Soluble guanylyl cyclase (sGC) heme oxidation (Fe 3+ ) leading to apo-sGC formation diminishes the ability of nitric oxide (NO) to bind sGC and generate intracellular cGMP levels needed for downstream protein kinase G activation and vessel relaxation. While several studies suggest that pathological oxidative stress drives sGC heme oxidation and apo-sGC formation, we report for the first time that resistance arteries, but not conduit arteries, contain a previously unrecognized pool of heme oxidized and/or apo-sGC in non-stressed conditions that can be activated independent of NO. Specifically, our vascular reactivity studies indicate that systemic resistance and pulmonary arteries are responsive to NO-independent sGC activator BAY 58-2667 at 2-3 log-fold lower concentrations than that of conduit aorta and renal arteries (n=4-5/ vascular bed). Further, mesenteric arteries treated with 1μM MitoTempol, a superoxide dismutase mimetic and mitochondrial anti-oxidant, show a decreased responsiveness to BAY 58-2667 (n=3-5/group). Notably, we have published evidence that cytochrome b5 reductase 3 (CYB5R3) acts as an sGC heme reductase (Fe 3+ -> Fe 2+ ) in cultured vascular smooth muscle cells. We recently performed vasoreactivity studies in transgenic CYB5R3 overexpression (OE CYB5R3) mice and show these mice have a significantly decreased responsiveness to BAY 58-2667 compared to controls irrespective of vascular bed (n=4-6/ group). Additionally, OE CYB5R3 mice exhibit a ~7mmHg decrease in pulse pressure and impaired blood pressure reduction in response to an acute injection of BAY 58-2667 as compared to controls (n=5/ group). Combined, these data indicate that mitochondria derived-reactive oxygen species and expression of CYB5R3 serve as a rheostat for modulating sensitivity to sGC activator BAY 58-2667 and vascular responsiveness in resistance arteries. Importantly, these results provide valuable insight into sGC activator therapy for treatment of hypertension and other cardiovascular related diseases.