Endothelial Targets of SOX17 in Pulmonary Arterial Hypertension: A Quantitative Proteomic Approach

Sangam, Shreya; Gupta, Akash; Yılmaz, Sevinc; Yuan, Jason X.‐J.; Langlais, Paul; Desai, Ankit A.

doi:10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a6748

D54. To Live and Let Die: The Endothelium in Pah 2019

DOI: 10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a6748

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Endothelial Targets of SOX17 in Pulmonary Arterial Hypertension: A Quantitative Proteomic Approach

Shreya Sangam

Akash Gupta

Sevinc Yılmaz

et al.

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2023

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“…We dissect the interactions between 16αOHE-mediated estrogen signaling, regulation of SOX17, and HIF2α signaling to establish the first link between sexual dimorphism, EC metabolism, and SOX17 genetics in PAH. Some of the results of these studies have been previously reported in the form of an abstract ( 22 , 23 ).…”

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confidence: 94%

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

Sangam

Sun

Schwantes‐An

et al. 2023

Am J Respir Crit Care Med

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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 ( Sox17 EC−/− ) deletion and attenuated by transgenic Tie2- Sox17 overexpression ( Sox17 Tg ). 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 Sox17 EC−/− and reduced in those from Sox17 Tg 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, Sox17 Tg 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.

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mentioning

confidence: 94%

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

Sangam

Sun

Schwantes‐An

et al. 2023

Am J Respir Crit Care Med

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Endothelial Targets of SOX17 in Pulmonary Arterial Hypertension: A Quantitative Proteomic Approach

Cited by 1 publication

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

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

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