Endothelial alpha globin is a nitrite reductase

T.C. Stevenson Keller(University of Virginia), Christophe Lechauve(St. Jude Children's Research Hospital), Alexander Keller(University of Virginia), Gilson Brás Broseghini-Filho(Universidade Federal do Espírito Santo), Joshua T. Butcher(Oklahoma State University), Henry R. Askew Page(University of Virginia), Aditi Islam(University of Virginia), Zhe Yin Tan(University of Virginia), Leon J. DeLalio(University of Virginia), Steven Brooks(National Institute of Allergy and Infectious Diseases), Poonam Sharma(University of Virginia), Kwangseok Hong(Chung-Ang University), Wenhao Xu(University of Virginia), Alessandra Simão Padilha(Universidade Federal do Espírito Santo), Claire A. Ruddiman(University of Virginia), Angela K. Best(University of Virginia), Edgar Macal(University of Virginia), Daniel B. Kim‐Shapiro(Wake Forest University), George J. Christ(University of Virginia), Zhen Yan(University of Virginia), Miriam M. Cortese‐Krott(Heinrich Heine University Düsseldorf), Karina Ricart(University of Alabama at Birmingham), Rakesh P. Patel(University of Alabama at Birmingham), Timothy P. Bender(University of Virginia), Swapnil K. Sonkusare(University of Virginia), Mitchell J. Weiss(St. Jude Children's Research Hospital), Hans Ackerman(National Institute of Allergy and Infectious Diseases), Linda Columbus(University of Virginia), Brant E. Isakson(University of Virginia)
Nature Communications
October 27, 2022
10.1038/s41467-022-34154-3
Cited by 34Open Access
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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.

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