SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics
Sangam S, Sun X, Schwantes-An TH, Yegambaram M, Lu Q, Shi Y, Cook T, Fisher A, Frump AL, Coleman A, Sun Y, Liang S, Crawford H, Lutz KA, Maun AD, Pauciulo MW, Karnes JH, Chaudhary KR, Stewart DJ, Langlais PR, Jain M, Alotaibi M, Lahm T, Jin Y, Gu H, Tang H, Nichols WC, Black SM, and Desai AA. SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics. Am J Respir Crit Care Med 2023.
American journal of respiratory and critical care medicine
RATIONALE/OBJECTIVES: Genetic studies suggest SOX17 deficiency increases pulmonary arterial hypertension (PAH) risk. Based on pathological roles of estrogen and hypoxia inducible factor 2α (HIF-2α) signaling in PA endothelial cells (PAECs), we hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF-2α inhibition.
METHODS: We used metabolic (seahorse) and promoter lucifer assays in PAECs along 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 PH was exacerbated by mice with conditional Tie2-Sox17 (Sox17EC-/-) deletion and attenuated by transgenic Tie2-Sox17 over-expression (Sox17Tg). Based on untargeted proteomics, metabolism was the top pathway altered by SOX17 deficiency in PAECs. Mechanistically, we found HIF-2α levels 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 HIF-2α overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16alpha-hydroxyestrone (16αOHE, a pathologic estrogen metabolite)-mediated repression of SOX17 promoter activity, Sox17Tg mice attenuated 16αOHE-mediated exacerbations of chronic hypoxic PH. Finally, in adjusted analyses in patients with PAH, we report novel associations between a SOX17 risk variant, rs10103692, with reduced plasma citrate levels (n=1326).
CONCLUSIONS: Cumulatively, SOX17 promotes mitochondrial bioenergetics and attenuates PAH, in part, via inhibition of HIF-2α. 16αOHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Medical Subject Headings
Male; Rats; Female; Mice; Animals; Hypertension, Pulmonary; Endothelial Cells; Lung; Pulmonary Artery; Hypoxia; Estrogens; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; HMGB Proteins; SOXF Transcription Factors
ePub ahead of print