SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics.

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.

• Authors: 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
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 207 Issue 8 Pg. 1055-1069 (04 15 2023) ISSN: 1535-4970 [Electronic] United States
• PMID: 36913491 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogens
• Sox17 protein, mouse
• HMGB Proteins
• SOXF Transcription Factors

Topics

• Male
• Rats
• Female
• Mice
• Animals
• Hypertension, Pulmonary (metabolism)
• Endothelial Cells (metabolism)
• Lung
• Pulmonary Artery
• Hypoxia (complications)
• Estrogens
• Pulmonary Arterial Hypertension (metabolism)
• Familial Primary Pulmonary Hypertension (complications)
• HMGB Proteins (metabolism)
• SOXF Transcription Factors (genetics)