TY - JOUR
T1 - SOX17 Deficiency Mediates Pulmonary Hypertension At the Crossroads of Sex, Metabolism, and Genetics
AU - Sangam, Shreya
AU - Sun, Xutong
AU - Schwantes-An, Tae Hwi
AU - Yegambaram, Manivannan
AU - Lu, Qing
AU - Shi, Yinan
AU - Cook, Todd
AU - Fisher, Amanda
AU - Frump, Andrea L.
AU - Coleman, Anna
AU - Sun, Yanan
AU - Liang, Shuxin
AU - Crawford, Howard
AU - Lutz, Katie A.
AU - Maun, Avinash D.
AU - Pauciulo, Michael W.
AU - Karnes, Jason H.
AU - Chaudhary, Ketul R.
AU - Stewart, Duncan J.
AU - Langlais, Paul R.
AU - Jain, Mohit
AU - Alotaibi, Mona
AU - Lahm, Tim
AU - Jin, Yan
AU - Gu, Haiwei
AU - Tang, Haiyang
AU - Nichols, William C.
AU - Black, Stephen M.
AU - Desai, Ankit A.
N1 - Publisher Copyright:
Copyright © 2023 by the American Thoracic Society.
PY - 2023/4/15
Y1 - 2023/4/15
N2 - 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 HIF2a (hypoxia-inducible factor 2a) 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 HIF2a 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 (Sox17EC2/2) 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 HIF2a concentrations were increased in the lungs of Sox17EC2/2 and reduced in those from Sox17Tg mice. Increased SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF2a overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16a-hydroxyestrone (16aOHE; a pathologic estrogen metabolite)-mediated repression of SOX17 promoter activity, Sox17Tg mice attenuated 16aOHE-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 HIF2a. 16aOHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH.
AB - 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 HIF2a (hypoxia-inducible factor 2a) 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 HIF2a 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 (Sox17EC2/2) 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 HIF2a concentrations were increased in the lungs of Sox17EC2/2 and reduced in those from Sox17Tg mice. Increased SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF2a overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16a-hydroxyestrone (16aOHE; a pathologic estrogen metabolite)-mediated repression of SOX17 promoter activity, Sox17Tg mice attenuated 16aOHE-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 HIF2a. 16aOHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH.
KW - 16a-hydroxyestrone
KW - SRY-related HMG-box 17
KW - hypoxia-inducible factor 2a
KW - metabolism
KW - pulmonary arterial hypertension
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U2 - 10.1164/rccm.202203-0450OC
DO - 10.1164/rccm.202203-0450OC
M3 - Article
C2 - 36913491
AN - SCOPUS:85154021311
SN - 1073-449X
VL - 207
SP - 1055
EP - 1069
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 8
ER -