Oral 15 Hydroxyeicosatetraenoic Acid Induces Pulmonary Hypertension in Mice by Triggering T Cell Dependent Endothelial Cell Apoptosis
Supplemental Digital Content is available in the text. 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.
Hypertension