Endothelial alpha globin is a nitrite reductase

T. C. Stevenson Keller, Christophe Lechauve, Alexander S. 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 Christ, Zhen Yan, Miriam M. Cortese-Krott, Karina Ricart, Rakesh Patel, Timothy P. Bender, Swapnil K. Sonkusare, Mitchell J. Weiss, Hans Ackerman, Linda Columbus and Brant E. Isakson ()
Additional contact information
T. C. Stevenson Keller: University of Virginia School of Medicine
Christophe Lechauve: St. Jude Children’s Research Hospital
Alexander S. Keller: University of Virginia School of Medicine
Gilson Brás Broseghini-Filho: University of Virginia School of Medicine
Joshua T. Butcher: Oklahoma State University
Henry R. Askew Page: University of Virginia School of Medicine
Aditi Islam: University of Virginia School of Medicine
Zhe Yin Tan: University of Virginia School of Medicine
Leon J. DeLalio: University of Virginia School of Medicine
Steven Brooks: National Institute of Allergy and Infectious Diseases
Poonam Sharma: University of Virginia
Kwangseok Hong: Chung-Ang University
Wenhao Xu: University of Virginia School of Medicine
Alessandra Simão Padilha: Federal University of Espirito Santo
Claire A. Ruddiman: University of Virginia School of Medicine
Angela K. Best: University of Virginia School of Medicine
Edgar Macal: University of Virginia School of Medicine
Daniel B. Kim-Shapiro: Wake Forest University
George Christ: University of Virginia
Zhen Yan: University of Virginia School of Medicine
Miriam M. Cortese-Krott: Heinrich Heine University
Karina Ricart: University of Alabama at Birmingham
Rakesh Patel: University of Alabama at Birmingham
Timothy P. Bender: University of Virginia School of Medicine
Swapnil K. Sonkusare: University of Virginia School of Medicine
Mitchell J. Weiss: St. Jude Children’s Research Hospital
Hans Ackerman: National Institute of Allergy and Infectious Diseases
Linda Columbus: University of Virginia School of Medicine
Brant E. Isakson: University of Virginia School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34154-3

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