Endothelial alpha globin is a nitrite reductase
T.C. Stevenson Keller, Christophe Lechauve, Alexander Keller, Gilson Brás Broseghini-Filho, Joshua T. Butcher, Henry R. Askew Page, Aditi Islam, Zhe Yin Tan, Leon J. DeLalio, Steven Brooks, Poonam Sharma, Kwangseok Hong, Wenhao Xu, Alessandra Simão Padilha, Claire A. Ruddiman, Angela K. Best, Edgar Macal, Daniel B. Kim‐Shapiro, George J. Christ, Zhen Yan, Miriam M. Cortese‐Krott, Karina Ricart, Rakesh P. Patel, Timothy P. Bender, Swapnil K. Sonkusare, Mitchell J. Weiss, Hans Ackerman, Linda Columbus, Brant E. Isakson
Abstract
Resistance artery vasodilation in response to hypoxia is essential for matching tissue oxygen and demand. In hypoxia, erythrocytic hemoglobin tetramers produce nitric oxide through nitrite reduction. We hypothesized that the alpha subunit of hemoglobin expressed in endothelium also facilitates nitrite reduction proximal to smooth muscle. Here, we create two mouse strains to test this: an endothelial-specific alpha globin knockout (EC Hba1Δ/Δ) and another with an alpha globin allele mutated to prevent alpha globin's inhibitory interaction with endothelial nitric oxide synthase (Hba1WT/Δ36-39). The EC Hba1Δ/Δ mice had significantly decreased exercise capacity and intracellular nitrite consumption in hypoxic conditions, an effect absent in Hba1WT/Δ36-39 mice. Hypoxia-induced vasodilation is significantly decreased in arteries from EC Hba1Δ/Δ, but not Hba1WT/Δ36-39 mice. Hypoxia also does not lower blood pressure in EC Hba1Δ/Δ mice. We conclude the presence of alpha globin in resistance artery endothelium acts as a nitrite reductase providing local nitric oxide in response to hypoxia.