Abstract 503: Smooth Muscle Cell Cytochrome B5 reductase < CYB5R3 > expression modulates vascular tone

Abstract

Hypertension is a major risk factor for cardiovascular-related morbidity and mortality. Nitric oxide (NO) resistance results in an inability of arterial blood vessels to relax contributing to hypertension. NO relaxes vascular smooth muscle cells (SMCs) by stimulating soluble guanylyl cyclase (sGC) to generate cyclic guanosine monophosphate (cGMP) which leads to downstream activation of protein kinase G (PKG) and vasodilation. Importantly, the sGC heme iron is required to be in the reduced (Fe 2+ ) state in order for NO to bind and activate sGC. When the sGC heme iron is oxidized (Fe 3+ ), sGC is insensitive to NO signaling for cGMP production, resulting in hypertension. We recently published evidence that NADH cytochrome b5 reductase 3 (CYB5R3) is a sGC heme reductase that maintains sGC in the reduced (Fe 2+ ), NO-sensitive state. Transient knockdown and pharmacological inhibition of CYB5R3 in SMCs blocks NO-mediated cGMP production and aortic relaxation. Combined, these data implicated CYB5R3 as a potential regulator of systemic blood pressure. To test this, we created tamoxifen-inducible SMC-specific CYB5R3 knockout mice (SMC CYB5R3 KO) and measured systemic blood pressure. We found SMC CYB5R3 KO mice have ~ 5 mmHg increase in mean arterial blood pressure at baseline relative to SMC CYB5R3 WT mice. Subsequently, Angiotensin II (Ang II) infusion resulted in a further ~ 15 mmHg increase in blood pressure respective to SMC CYB5R3 WT mice. Future studies will test whether SMC CYB5R3 may confer vascular protection against Ang II-induced HTN, vessel fibrosis, and SMC dysfunction by maintaining sGC in the reduced, NO sensitive state .