Shreya Sangam, Xutong Sun, Tae-Hwi Schwantes-An, Manivannan Yegambaram, Qing Lu, Yinan Shi, Todd Cook, Amanda Fisher, Andrea L. Frump, Anna Coleman, Yanan Sun, Shuxin Liang, Howard Crawford, Katie A. Lutz, Avinash D. Maun, Michael W. Pauciulo, Jason H. Karnes, Ketul R. Chaudhary, Duncan J. Stewart, Paul R. Langlais, Mohit Jain, Mona Alotaibi, Tim Lahm, Yan Jin, Haiwei Gu, Haiyang Tang, William C. Nichols, Stephen M. Black, Ankit A. Desai
Florida International University. Indiana University. The First Affiliated Hospital of Guangzhou Medical University. Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine. Northwest A & F University. Henry Ford Hospital. Dalhousie University. Ottawa Hospital Research Institute. University of Arizona. University of California, San Diego. National Jewish Health.
United States, China and Canada
American Journal of Respiratory and Critical Care Medicine
Am J Respir Crit Care Med 2023; 207: 1055-1069
DOI: 10.1164/rccm.202203-0450OC
Abstract
Rationale: Genetic studies suggest that SOX17 (SRY-related HMG-box 17) deficiency increases pulmonary arterial hypertension (PAH) risk.
Objectives: On the basis of pathological roles of estrogen and HIF2α (hypoxia-inducible factor 2α) signaling in pulmonary artery endothelial cells (PAECs), we hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF2α inhibition.
Methods: We used metabolic (Seahorse) and promoter luciferase assays in PAECs together with the chronic hypoxia murine model to test the hypothesis.
Measurements and Main Results: Sox17 expression was reduced in PAH tissues (rodent models and from patients). Chronic hypoxic pulmonary hypertension was exacerbated by mice with conditional Tie2-Sox17 (Sox17EC-/-) deletion and attenuated by transgenic Tie2-Sox17 overexpression (Sox17Tg). On the basis of untargeted proteomics, metabolism was the top pathway altered by SOX17 deficiency in PAECs. Mechanistically, we found that HIF2α concentrations were increased in the lungs of Sox17EC-/- and reduced in those from Sox17Tg mice. Increased SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF2α overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16α-hydroxyestrone (16αOHE; a pathologic estrogen metabolite)-mediated repression of SOX17 promoter activity, Sox17Tg mice attenuated 16αOHE-mediated exacerbations of chronic hypoxic pulmonary hypertension. Finally, in adjusted analyses in patients with PAH, we report novel associations between a SOX17 risk variant, rs10103692, and reduced plasma citrate concentrations (n = 1,326).
Conclusions: Cumulatively, SOX17 promotes mitochondrial bioenergetics and attenuates PAH, in part, via inhibition of HIF2α. 16αOHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH.
Category
Genetic Factors Associated with Pulmonary Vascular Disease
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes