Nitric Oxide and Endothelial Function in Patients with Malaria

National Institute Of Allergy And Infectious Diseases

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Abstract

Impaired nitric oxide synthase-dependent vasodilation is a hallmark of vascular diseases from atherosclerosis to malaria. Efforts to restore nitric oxide (NO) signaling have been limited by an incomplete understanding of NO regulation in human arteries. A promising new paradigm has emerged from pre-clinical studies in which endothelial alpha globin restricts the release of NO by interacting with endothelial NO synthase (eNOS). We examined this pathway in human resistance arteries, and discovered that humans express not only alpha but also beta globin, which together form tetrameric hemoglobin that interacts directly with eNOS to regulate NO signaling. To understand the functional consequences of this previously unrecognized hemoglobin-eNOS complex, we used molecular modeling and simulation to predict the key interfaces between these two proteins. The simulations indicated that glutamic acid at position six of beta globin participates in key charge complementarities with arginines 97 and 98 of eNOS. Disruption of these interactions with a mimetic peptide increased NOS-dependent signaling and dilated human arteries ex vivo. Furthermore, arteries obtained from healthy individuals with sickle cell trait, in whom the glutamic acid at position six is replaced by valine, exhibited the same phenotype of increased NOS-dependent signaling. Together these experiments imply that the sickle cell trait variant increases NOS-dependent NO signaling by disrupting the interface between hemoglobin and eNOS. The alpha subunit of hemoglobin also participates in functional interactions with eNOS. Disruption of alpha globin-eNOS interactions increased NOS-dependent NO signaling and dilated human arteries ex vivo. Furthermore, we found that a common alpha globin gene deletion was associated with decreased expression of alpha globin in the artery wall and increased NOS-dependent vasodilation. At the population level, we found the alpha globin gene deletion to be associated with lower blood pressure among Cambodian children. These novel findings have broad implications for human health. We define novel vascular phenotypes of increased NOS-dependent NO signaling associated with sickle cell trait and alpha thalassemia. These genetic variants may have been selected for because of enhanced endothelial NO signaling which would mitigate endothelial dysfunction in severe malaria. We identify specific interfaces within the hemoglobin-eNOS complex that can be targeted to increase endothelial NO signaling in human arteries. This approach could be used to treat severe malaria and other conditions of impaired NO bioavailability, such as cardiometabolic diseases.