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 ( 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.

Orphan Nuclear Receptor Family 4A (NR4A) Members NR4A2 and NR4A3 Selectively Modulate Elements of the Monocyte Response to Buffered Hypercapnia

“…SOX17 is a key transcription factor involved in development that affects the cardiovascular system and several endoderm-derived organs [ 44 ]. SOX17 deficiency is linked to pulmonary arterial hypertension (PAH) risk via interactions with Hypoxia Inducible Factor 2 Alpha (HIF-2α) [ 45 ]. TAL1 is also a leukaemia associated transcription factor associated with hematopoiesis [ 45 ], which can act in complex with LMO2, a LIM-domain protein [ 46 ].…”

E2F1 Mediates SOX17 Deficiency–Induced Pulmonary Hypertension

“…15 Walters et al demonstrated that SOX17 enhancer variants lead to downregulation of SOX17 and result in disturbed lung ECs function and PAH through different binding of HOXA5 and ROR-α. Sangam et al 16 reported that SOX17 deficiency inhibits mitochondrial bioenergetics and induces PAH partly via HIF-2α signaling. Zou et al 32 identified SOX17-associated exosomes including microR-224-5p and microR-361-3p improve endothelial function.…”

“…14 Recent study showed that Sox17 deficiency promoted PH in mice via hepatocyte grow factor (HGF)/c-Met signaling or HIF-2α. 15,16 CRISPR/Cas9-mediated Sox17 enhancer deletion in mice worsened PH. 17 Nevertheless, the exact role of genetic variants or mutation in SOX17 in the contribution of PH remains unclear.…”

The Impact of CC16 on Pulmonary Epithelial-Driven Host Responses during Mycoplasma pneumoniae Infection in Mouse Tracheal Epithelial Cells

“…Progenesis QI for proteomics software (version 2.4, Nonlinear Dynamics Ltd., Newcastle upon Tyne, UK) was used to perform ion-intensity based label-free quantification as previously described [63][64][65][66]. In brief, in an automated format, .raw files were imported and converted into two-dimensional maps (y-axis = time, x-axis = m/z) followed by the selection of a reference run for alignment purposes.…”