Redox-Regulation of α-Globin in Vascular Physiology.

Laurent Kiger,Abdullah Freiwan,Brant E Isakson,Mitchell J Weiss,Christophe Lechauve,Alfonso G Fernandez,Heather Tillman,Julia Keith

doi:10.3390/antiox11010159

Abstract

Interest in the structure, function, and evolutionary relations of circulating and intracellular globins dates back more than 60 years to the first determination of the three-dimensional structure of these proteins. Non-erythrocytic globins have been implicated in circulatory control through reactions that couple nitric oxide (NO) signaling with cellular oxygen availability and redox status. Small artery endothelial cells (ECs) express free α-globin, which causes vasoconstriction by degrading NO. This reaction converts reduced (Fe2+) α-globin to the oxidized (Fe3+) form, which is unstable, cytotoxic, and unable to degrade NO. Therefore, (Fe3+) α-globin must be stabilized and recycled to (Fe2+) α-globin to reinitiate the catalytic cycle. The molecular chaperone α-hemoglobin-stabilizing protein (AHSP) binds (Fe3+) α-globin to inhibit its degradation and facilitate its reduction. The mechanisms that reduce (Fe3+) α-globin in ECs are unknown, although endothelial nitric oxide synthase (eNOS) and cytochrome b5 reductase (CyB5R3) with cytochrome b5 type A (CyB5a) can reduce (Fe3+) α-globin in solution. Here, we examine the expression and cellular localization of eNOS, CyB5a, and CyB5R3 in mouse arterial ECs and show that α-globin can be reduced by either of two independent redox systems, CyB5R3/CyB5a and eNOS. Together, our findings provide new insights into the regulation of blood vessel contractility.

Highlights

IntroductionThe globin protein superfamily shares an active motif conserved across eukaryotes, bacteria, and archaea [1,2,3]
Introduction published maps and institutional affilThe globin protein superfamily shares an active motif conserved across eukaryotes, bacteria, and archaea [1,2,3]
Primordial globin proteins are believed to have arisen in low-O2 environments as O2 sensors and/or enzymatic nitric oxide (NO) scavengers before evolving into red blood cells (RBCs) O2 transporters [39], and the evolution of globin genes over time provides a context for understanding the diverse roles of globins in vascular physiprovides a context for understanding the diverse roles of globins in vascular physiology

Summary

Introduction

The globin protein superfamily shares an active motif conserved across eukaryotes, bacteria, and archaea [1,2,3]. Neuroglobin and cytoglobin contain hexacoordinate heme, in which the sixth coordinate position of the central iron atom is bound by a globin amino acid that competes for external ligand binding [6]. These globins, cytoglobin, may serve as reversible ligand carriers and may participate in redox reactions, but their biological functions are currently unclear [7]. Each member of the globin family of proteins has a distinct pattern of tissue expression, subcellular localization, and affinity for external iations

Methods

Discussion

Conclusion