Loss of alpha‐globin genes in human subjects is associated with improved nitric oxide‐mediated vascular perfusion

Abstract

Alpha thalassemia is a hemoglobinopathy due to decreased production of the α‐globin protein from loss of up to four α‐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 α‐globin genes have been known to have reduced risk of morbid outcomes, but the underlying mechanism is unknown. While α‐globin gene deletions affect sickle red cell deformability, the α‐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 α‐globin due to α‐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 α‐globin genes and 12 healthy controls). Flow‐mediated dilation was significantly higher in subjects with α‐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 α‐globin gene status. This may explain the beneficial effect of α‐globin gene loss in sickle cell disease and suggests that α‐globin gene status may play a role in other vascular diseases.

Hemoglobin Interacts with Endothelial Nitric Oxide Synthase to Regulate Vasodilation in Human Resistance Arteries

“…For example, a recent study found that healthy individuals with alpha globin gene deletions have increased nitric oxide-mediated vascular perfusion. 48 We recently discovered alpha globin gene deletions to be associated with protection from chronic kidney disease and end-stage kidney disease. 49 These associations were independent of sickle cell trait and hemoglobin level, raising the possibility that protection is conferred via mechanisms involving the vascular functions of alpha globin.…”

Endothelial alpha globin is a nitrite reductase

“…Negative regulation of NO signaling by endothelial alpha globin is O 2 dependent, as both eNOS production of NO and deactivation of NO by alpha globin (producing nitrate, NO 3 − ) require O 2 . Recent work from human studies confirmed an role for endothelial alpha globin in NO catabolism, as alpha thalassemic individuals demonstrated increased flow-mediated dilation 14 .…”

Loss of alpha globin genes is associated with improved microvascular function in patients with sickle cell anemia

“…Recently, motivated by in vitro data on α-globin in the myoendothelial junction, 5,6 Denton and colleagues showed in non-anemic, non-SCA subjects that flow-mediated vasodilation, a well-known measure of NO-mediated vascular function, was significantly better in α-trait subjects than in subjects without α-trait. 8 Thus, the mechanism proposed in vitro whereby α-globin expressed in the endothelial cells would bind, react with and oxidize NO to form nitrate, thus reducing NO levels and the resultant vasodilatory effects of NO, seems to be operative not only in non-SCA subjects but also in SCA patients. Our results suggest that the protective effect of α-trait from the development of several chronic complications in SCA could, in addition to its known effects on the RBC, be due to the effect of α-globin on the vascular system through its ability to regulate the NO diffusion from the endothelium to the smooth muscle cells of the vascular wall.…”