Nitrite Regulates Hypoxic Vasodilation via Myoglobin-Dependent Nitric Oxide Generation

作者：Totzeck Matthias; Hendgen Cotta Ulrike B; Luedike Peter; Berenbrink Michael; Klare Johann P; Steinhoff Heinz Juergen; Semmler Dominik; Shiva Sruti; Williams Daryl; Kipar Anja; Gladwin Mark T; Schrader Juergen; Kelm Malte; Cossins Andrew R; Rassaf Tienush^*

来源：Circulation, 2012, 126(3): 325-+.

DOI：10.1161/CIRCULATIONAHA.111.087155

• hypoxic vasodilation
• myoglobin
• nitrite

Background-Hypoxic vasodilation is a physiological response to low oxygen tension that increases blood supply to match metabolic demands. Although this response has been characterized for %26gt;100 years, the underlying hypoxic sensing and effector signaling mechanisms remain uncertain. We have shown that deoxygenated myoglobin in the heart can reduce nitrite to nitric oxide (NO center dot) and thereby contribute to cardiomyocyte NO center dot signaling during ischemia. On the basis of recent observations that myoglobin is expressed in the vasculature of hypoxia-tolerant fish, we hypothesized that endogenous nitrite may contribute to physiological hypoxic vasodilation via reactions with vascular myoglobin to form NO center dot. %26lt;br%26gt;Methods and Results-We show in the present study that myoglobin is expressed in vascular smooth muscle and contributes significantly to nitrite-dependent hypoxic vasodilation in vivo and ex vivo. The generation of NO center dot from nitrite reduction by deoxygenated myoglobin activates canonical soluble guanylate cyclase/cGMP signaling pathways. In vivo and ex vivo vasodilation responses, the reduction of nitrite to NO center dot, and the subsequent signal transduction mechanisms were all significantly impaired in mice without myoglobin. Hypoxic vasodilation studies in myoglobin and endothelial and inducible NO synthase knockout models suggest that only myoglobin contributes to systemic hypoxic vasodilatory responses in mice. %26lt;br%26gt;Conclusions-Endogenous nitrite is a physiological effector of hypoxic vasodilation. Its reduction to NO center dot via the heme globin myoglobin enhances blood flow and matches O-2 supply to increased metabolic demands under hypoxic conditions. (Circulation. 2012; 126: 325-334.)

• 出版日期2012-7-17