Oral 15-Hydroxyeicosatetraenoic Acid Induces Pulmonary Hypertension in Mice by Triggering T Cell-Dependent Endothelial Cell Apoptosis

Grégoire Ruffenach, Ellen O'Connor, Mylène Vaillancourt, Jason Hong, Nancy Cao, Shervin Sarji, Shayan Moazeni, Jeremy Papesh, Victor Grijalva, Christine M. Cunningham, Le Shu, Arnab Chattopadhyay, Shuchita Tiwari, Olaf Mercier, Frédéric Perros, Soban Umar, Xia Yang, Aldrin V. Gomes, Alan M. Fogelman, Srinivasa T. ReddyMansoureh Eghbali

Research output: Contribution to journalArticle

Abstract

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased mean pulmonary arterial pressure. Elevated plasma and lung concentrations of oxidized lipids, including 15-hydroxyeicosatetraenoic acid (15-HETE), have been demonstrated in patients with PAH and animal models. We previously demonstrated that feeding mice with 15-HETE is sufficient to induce pulmonary hypertension, but the mechanisms remain unknown. RNA sequencing data from the mouse lungs on 15-HETE diet revealed significant activation of pathways involved in both antigen processing and presentation and T cell-mediated cytotoxicity. Analysis of human microarray from patients with PAH also identified activation of identical pathways compared with controls. We show that in both 15-HETE-fed mice and patients with PAH, expression of the immunoproteasome subunit 5 is significantly increased, which was concomitant with an increase in the number of CD8/CD69 (cluster of differentiation 8 / cluster of differentiation 69) double-positive cells, as well as pulmonary arterial endothelial cell apoptosis in mice. Human pulmonary arterial endothelial cells cultured with 15-HETE were more prone to apoptosis when exposed to CD8 cells. Cultured intestinal epithelial cells secreted more oxidized lipids in response to 15-HETE, which is consistent with accumulation of circulating oxidized lipids in 15-HETE-fed mice. Administration of an apoA-I (apolipoprotein A-I) mimetic peptide, Tg6F (transgenic 6F), which is known to prevent accumulation of circulating oxidized lipids, not only inhibited pulmonary arterial endothelial cell apoptosis but also prevented and rescued 15-HETE-induced pulmonary hypertension in mice. In conclusion, our results suggest that (1) 15-HETE diet induces pulmonary hypertension by a mechanism that involves oxidized lipid-mediated T cell-dependent pulmonary arterial endothelial cell apoptosis and (2) Tg6F administration may be a novel therapy for treating PAH.

Original languageEnglish (US)
Pages (from-to)985-996
Number of pages12
JournalHypertension
DOIs
StateAccepted/In press - 2020

Keywords

  • endothelial cells
  • hypertension, pulmonary
  • inflammation
  • proteasome endopeptidase complex
  • T lymphocytes

ASJC Scopus subject areas

  • Internal Medicine

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    Ruffenach, G., O'Connor, E., Vaillancourt, M., Hong, J., Cao, N., Sarji, S., Moazeni, S., Papesh, J., Grijalva, V., Cunningham, C. M., Shu, L., Chattopadhyay, A., Tiwari, S., Mercier, O., Perros, F., Umar, S., Yang, X., Gomes, A. V., Fogelman, A. M., ... Eghbali, M. (Accepted/In press). Oral 15-Hydroxyeicosatetraenoic Acid Induces Pulmonary Hypertension in Mice by Triggering T Cell-Dependent Endothelial Cell Apoptosis. Hypertension, 985-996. https://doi.org/10.1161/HYPERTENSIONAHA.120.14697