Endothelial-Mesenchymal Transition Drives Expression of CD44 Variant and xCT in Pulmonary Hypertension
Endothelial-Mesenchymal Transition Drives Expression of CD44 Variant and xCT in Pulmonary Hypertension
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DOI：
10.1165/rcmb.2018-0231oc
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发表时间：
2019-09-01
影响因子：
6.4
通讯作者：
Sano, Motoaki
中科院分区：
文献类型：
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作者：
Isobe, Sarasa;Kataoka, Masaharu;Sano, Motoaki
肺动脉高压（PAH）的发病机制与肿瘤的发生有相似之处。一种CD 44变体（CD 44 v）同种型，CD 44 v8 -10，结合并稳定胱氨酸转运蛋白亚基（xCT），产生还原型谷胱甘肽，从而增强癌症干细胞的抗氧化防御。柳氮磺胺吡啶对xCT的药理学抑制可抑制肿瘤生长、生存和化疗耐药性。我们研究了CD 44 v-xCT轴是否有助于PAH发病机制。CD 44 v主要表达在PAH影响的肺小动脉新生内膜层的内皮-间充质转化（EndMT）样细胞上。在体外，作为EndMT的结果，诱导CD 44标准形式和CD 44 v。在接受EndMT的人肺动脉内皮细胞中，CD 44 v（+）细胞在其细胞表面显示出高水平的xCT表达和高浓度的谷胱甘肽存活。这使得CD 44 v（+）细胞成为柳氮磺胺吡啶最脆弱的靶细胞。CD 44 v（+）xCT（hi）细胞表现出最高水平的促炎细胞因子、抗氧化酶、抗凋亡分子和细胞周期蛋白依赖性激酶抑制剂的表达。在Sugen 5416/低氧小鼠模型中，CD 44 v（+）细胞存在于增厚的肺血管壁中。柳氮磺胺吡啶的给药与“Sugen 5416”给药同时开始（预防模型）或在肺动脉高压发展之后开始（逆转模型），减弱了肺血管的肌化，降低了炎症标志物的表达，并降低了右心室收缩压，同时减少了CD 44 v（+）细胞。总之，CD 44 v（+）xCT（hi）细胞出现在EndMT期间和肺动脉高压组织中。柳氮磺胺吡啶有望成为PAH的新型治疗药物，最有可能靶向EndMT衍生的CD 44 v（+）xCT（hi）细胞。
Pulmonary arterial hypertension (PAH) pathogenesis shares similarities with carcinogenesis. One CD44 variant (CD44v) isoform, CD44v8-10, binds to and stabilizes the cystine transporter subunit (xCT), producing reduced glutathione and thereby enhancing the antioxidant defense of cancer stem cells. Pharmacological inhibition of xCT by sulfasalazine suppresses tumor growth, survival, and resistance to chemotherapy. We investigated whether the CD44v-xCT axis contributes to PAH pathogenesis. CD44v was predominantly expressed on endothelial-to-mesenchymal transition (EndMT)-like cells in the neointimal layer of PAH affected pulmonary arterioles. In vitro, CD44 standard form and CD44v were induced as a result of EndMT. Among human pulmonary artery endothelial cells that have undergone EndMT, CD44v(+) cells showed high levels of xCT expression on their cell surfaces and high concentrations of glutathione for survival. This made CD44v(+) cells the most vulnerable target for sulfasalazine. CD44v(+) xCT(hi) cells showed the highest expression levels of proinflammatory cytokines, antioxidant enzymes, antiapoptotic molecules, and cyclin-dependent kinase inhibitors. In the Sugen5416/hypoxia mouse model, CD44v(+) cells were present in the thickened pulmonary vascular wall. The administration of sulfasalazine started either at the same time as "Sugen5416" administration (a prevention model) or after the development of pulmonary hypertension (a reversal model) attenuated the muscularization of the pulmonary vessels, decreased the expression of markers of inflammation, and reduced the right ventricular systolic pressure, while reducing CD44v(+) cells. In conclusion, CD44v(+) xCT(hi) cells appear during EndMT and in pulmonary hypertension tissues. Sulfasalazine is expected to be a novel therapeutic agent for PAH, most likely targeting EndMT-derived CD44v(+) xCT(hi) cells.