RGD Reference Report - SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics. - Rat Genome Database

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

Authors: Sangam, Shreya  Sun, Xutong  Schwantes-An, Tae-Hwi  Yegambaram, Manivannan  Lu, Qing  Shi, Yinan  Cook, Todd  Fisher, Amanda  Frump, Andrea L  Coleman, Anna  Sun, Yanan  Liang, Shuxin  Crawford, Howard  Lutz, Katie A  Maun, Avinash D  Pauciulo, Michael W  Karnes, Jason H  Chaudhary, Ketul R  Stewart, Duncan J  Langlais, Paul R  Jain, Mohit  Alotaibi, Mona  Lahm, Tim  Jin, Yan  Gu, Haiwei  Tang, Haiyang  Nichols, William C  Black, Stephen M  Desai, Ankit A 
Citation: Sangam S, etal., Am J Respir Crit Care Med. 2023 Apr 15;207(8):1055-1069. doi: 10.1164/rccm.202203-0450OC.
RGD ID: 329853317
Pubmed: PMID:36913491   (View Abstract at PubMed)
PMCID: PMC10112457   (View Article at PubMed Central)
DOI: DOI:10.1164/rccm.202203-0450OC   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SOX17HumanPulmonary Arterial Hypertension  IEP protein:decreased expression:lung endothelium (human)RGD 
Sox17RatPulmonary Arterial Hypertension  ISOSOX17 (Homo sapiens)protein:decreased expression:lung endothelium (human)RGD 
Sox17MousePulmonary Arterial Hypertension  ISOSOX17 (Homo sapiens)protein:decreased expression:lung endothelium (human)RGD 
SOX17Humanpulmonary hypertension  ISOSox17 (Rattus norvegicus)protein:decreased expression:lung (rat)RGD 
Sox17Ratpulmonary hypertension  IEP protein:decreased expression:lung (rat)RGD 
Sox17Mousepulmonary hypertension  ISOSox17 (Rattus norvegicus)protein:decreased expression:lung (rat)RGD 
SOX17HumanPulmonary Hypertension, Hypoxia-Induced exacerbatesISOSox17 (Mus musculus) RGD 
Sox17RatPulmonary Hypertension, Hypoxia-Induced exacerbatesISOSox17 (Mus musculus) RGD 
Sox17MousePulmonary Hypertension, Hypoxia-Induced exacerbatesIMP  RGD 

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SOX17Humanmonocrotaline decreases expression ISOSox17 (Rattus norvegicus)Monocrotaline decreases expression of Sox17 protein in the lungRGD 
Sox17Ratmonocrotaline decreases expression EXP Monocrotaline decreases expression of Sox17 protein in the lungRGD 
Sox17Mousemonocrotaline decreases expression ISOSox17 (Rattus norvegicus)Monocrotaline decreases expression of Sox17 protein in the lungRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Sox17Ratresponse to alkaloid  IEP monocrotalineRGD 

Objects Annotated

Genes (Rattus norvegicus)
Sox17  (SRY-box transcription factor 17)

Genes (Mus musculus)
Sox17  (SRY (sex determining region Y)-box 17)

Genes (Homo sapiens)
SOX17  (SRY-box transcription factor 17)


Additional Information