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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DOI：
10.1164/rccm.202203-0450oc
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发表时间：
2023-04-15
影响因子：
24.7
通讯作者：
中科院分区：
文献类型：
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遗传学研究表明，SOX 17（SRY相关HMG盒17）缺乏会增加肺动脉高压（PAH）的风险。基于雌激素和HIF 2 α（缺氧诱导因子2α）信号在肺动脉内皮细胞（PAECs）中的病理作用，我们假设SOX 17是雌激素信号的靶点，通过抑制HIF 2 α促进线粒体功能并减弱PAH的发展。我们使用代谢（海马）和启动子荧光素酶测定PAEC与慢性缺氧小鼠模型来测试的假设。PAH组织（啮齿动物模型和患者）中Sox 17表达减少。慢性低氧性肺动脉高压在条件性Tie 2-Sox 17（Sox 17 EC-/-）缺失的小鼠中加重，在转基因Tie 2-Sox 17过表达（Sox 17 Tg）的小鼠中减轻。基于非靶向蛋白质组学，代谢是PAECs中SOX 17缺陷改变的首要途径。从机制上讲，我们发现Sox 17 EC −/−小鼠肺中的HIF 2 α浓度增加，而Sox 17 Tg小鼠肺中的HIF 2 α浓度降低。SOX 17的增加促进了PAEC的氧化磷酸化和线粒体功能，HIF 2 α的过表达部分减弱了这一作用。雄性大鼠肺中Sox 17的表达高于雌性大鼠，表明雌激素信号转导的抑制作用。支持16α-羟基雌酮（16αOHE;一种病理性雌激素代谢产物）介导的SOX 17启动子活性抑制，Sox 17 Tg小鼠减弱了16α OHE介导的慢性缺氧性肺动脉高压加重。最后，在PAH患者的校正分析中，我们报告了SOX 17风险变体rs 10103692与血浆柠檬酸盐浓度降低之间的新相关性（n = 1，326）。SOX 17通过抑制HIF 2 α，逐渐促进线粒体生物能量学并部分减弱PAH。16αOHE通过下调SOX 17介导PAH的发展，将PAH中的性二型性和SOX 17遗传学联系起来。
Genetic studies suggest that SOX17 (SRY-related HMG-box 17) deficiency increases pulmonary arterial hypertension (PAH) risk. 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. We used metabolic (Seahorse) and promoter luciferase assays in PAECs together with the chronic hypoxia murine model to test the hypothesis. 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). 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.
影响因子：
3.7
作者：
Jonatan D;Spence JR;Method AM;Kofron M;Sinagoga K;Haataja L;Arvan P;Deutsch GH;Wells JM
通讯作者：
Wells JM