Endothelial-mesenchymal transition drives expression of CD44 variant and xCT in pulmonary hypertension

Sarasa Isobe, Masaharu Kataoka, Jin Endo, Hidenori Moriyama, Shogo Okazaki, Kenji Tsuchihashi, Yoshinori Katsumata, Tsunehisa Yamamoto, Kosuke Shirakawa, Naohiro Yoshida, Masayuki Shimoda, Tomohiro Chiba, Takashi Masuko, Yoji Hakamata, Eiji Kobayashi, Hideyuki Saya, Keiichi Fukuda, Motoaki Sano

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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+xCThi 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+xCThi 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+xCThi cells.

Original languageEnglish
Pages (from-to)367-379
Number of pages13
JournalAmerican journal of respiratory cell and molecular biology
Volume61
Issue number3
DOIs
Publication statusPublished - 2019 Jan 1

Keywords

  • CD44 variant isoform
  • Endothelial-mesenchymal transition
  • Pulmonary arterial hypertension
  • Sulfasalazine
  • xCT

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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