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

Hypertension. 2020 Sep;76(3):985-996. doi: 10.1161/HYPERTENSIONAHA.120.14697. Epub 2020 Jul 27.


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.

Keywords: T lymphocytes; endothelial cells; hypertension, pulmonary; inflammation; proteasome endopeptidase complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Apoptosis* / immunology
  • Cell Differentiation
  • Cell Proliferation
  • Endothelial Cells* / drug effects
  • Endothelial Cells* / metabolism
  • Hydroxyeicosatetraenoic Acids / metabolism*
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / prevention & control
  • Immunologic Factors / pharmacology
  • Immunoproteins
  • Lipid Metabolism / drug effects
  • Mice
  • Peptides / pharmacology*
  • Proteasome Endopeptidase Complex
  • Pulmonary Artery* / metabolism
  • Pulmonary Artery* / pathology
  • T-Lymphocytes


  • 6F peptide
  • Hydroxyeicosatetraenoic Acids
  • Immunologic Factors
  • Immunoproteins
  • Peptides
  • 15-hydroxy-5,8,11,13-eicosatetraenoic acid
  • Proteasome Endopeptidase Complex