Loss Of Alpha Globin Genes In Human Subjects Is Associated With Improved Nitric Oxide-Mediated Vascular Perfusion

Alpha thalassemia is a hemoglobinopathy due to decreased production of the alpha-globin protein from loss of up to four alpha-globin genes, with one or two missing in the trait phenotype. Individuals with sickle cell disease who co-inherit the loss of one or two alpha-globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While alpha-globin gene deletions affect sickle red cell deformability, the alpha-globin genes and protein are also present in the endothelial wall of human arterioles and participate in nitric oxide scavenging during vasoconstriction. Decreased production of alpha-globin due to alpha-thalassemia trait may thereby limit nitric oxide scavenging and promote vasodilation. To evaluate this potential mechanism, we performed flow-mediated dilation and microvascular post-occlusive reactive hyperemia in 27 human subjects (15 missing one or two alpha-globin genes and 12 healthy controls). Flow-mediated dilation was significantly higher in subjects with alpha-trait after controlling for age (P = .0357), but microvascular perfusion was not different between groups. As none of the subjects had anemia or hemolysis, the improvement in vascular function could be attributed to the difference in alpha-globin gene status. This may explain the beneficial effect of alpha-globin gene loss in sickle cell disease and suggests that alpha-globin gene status may play a role in other vascular diseases.