Sickle Trait and Alpha Thalassemia Increase NOS-Dependent Vasodilation of Human Arteries Through Disruption of Endothelial Hemoglobin-eNOS Interactions

• DOI: 10.1161/circulationaha.123.066003
• Publication Date: 2024-12-05T10:00:48Z
• Authors: Steven D. Brooks; A. Parker Ruhl; Xianke Zeng; Phillip Cruz; Sergio A. Hassan; Olena Kamenyeva; Md Abdul Hakim; Lauryn A. Ridley; Bianca M. Nagata; Juraj Kabat; Sundar Ganesan; Rachel L. Smith; Mary Jackson; Jessica Nino de R...; Alison J. McLure; Jarrett M. Jackson; Robert O. Emeh; Naomi Tesfuzigta; Kyeisha Laurence; Stacy Joyce; Christina Yek; Sophana Chea; Derron A. Alves; Brant E. Isakson; Jessica Manning; Jeremy L. Davis; Hans C. Ackerman
• Keywords: Sickle cell trait; Endothelial NOS

BACKGROUND: Severe malaria is associated with impaired nitric oxide (NO) synthase (NOS)–dependent vasodilation, and reversal of this deficit improves survival in murine models. Malaria might have selected for genetic polymorphisms that increase endothelial NO signaling now contribute to heterogeneity vascular function among humans. One protein potentially alpha globin, which, mouse models, interacts NOS (eNOS) negatively regulate signaling. We sought evaluate the impact globin gene deletions on unexpectedly found human arteries use not only but also beta eNOS. METHODS: The eNOS-hemoglobin complex was characterized by multiphoton imaging, expression analysis, coimmunoprecipitation studies resistance arteries. Novel contacts between eNOS hemoglobin were mapped using molecular modeling simulation. Pharmacological or disruption evaluated pressure myography. association deletion blood assessed a population study. RESULTS: Alpha transcripts detected layer artery wall. Imaging colocalized proteins at myoendothelial junctions. Immunoprecipitation demonstrated form cytochrome b5 reductase. Modeling predicted charged glutamic acids positions 6 7 interact positively arginines 97 98 Arteries from donors acid–to–valine substitution position (sickle trait) exhibited increased NOS-dependent vasodilation. decreased arterial expression, lower pressure. Mimetic peptides targeted interactions recapitulated effects these variants vasoreactivity. CONCLUSIONS: subunits restrict Malaria-protective alter structure are Targeting hemoglobin-eNOS interface could improve diseases dysfunction such as severe chronic cardiovascular conditions.