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.