miR-150-PTPMT1-cardiolipin signaling in pulmonary arterial hypertension
File(s)
Published version
Supporting information
Author(s)
Type
Journal Article
Abstract
Circulating levels of endothelial miR-150 are reduced in pulmonary arterial hypertension (PAH) and act as an independent predictor of patient survival, but links between endothelial miR-150 and vascular dysfunction are not well understood. We studied the effects of endothelial miR-150 supplementation and inhibition in PAH mice and cells from patients with idiopathic PAH. The role of selected mediators of miR-150 identified by RNA sequencing was evaluated in vitro and in vivo. Endothelium-targeted miR-150 delivery prevented the disease in Sugen/hypoxia mice, while endothelial knockdown of miR-150 had adverse effects. miR-150 target genes revealed significant associations with PAH pathways, including proliferation, inflammation, and phospholipid signaling, with PTEN-like mitochondrial phosphatase (PTPMT1) most markedly altered. PTPMT1 reduced inflammation and apoptosis and improved mitochondrial function in human pulmonary endothelial cells and blood-derived endothelial colony-forming cells from idiopathic PAH. Beneficial effects of miR-150 in vitro and in vivo were linked with PTPMT1-dependent biosynthesis of mitochondrial phospholipid cardiolipin and reduced expression of pro-apoptotic, pro-inflammatory, and pro-fibrotic genes, including c-MYB, NOTCH3, transforming growth factor β (TGF-β), and Col1a1. In conclusion, we are the first to show that miR-150 supplementation attenuates pulmonary endothelial damage induced by vascular stresses and may be considered as a potential therapeutic strategy in PAH.
Date Issued
2021-03-01
Date Acceptance
2020-10-28
Citation
Molecular Therapy : Nucleic Acids, 2021, 23, pp.142-153
ISSN
2162-2531
Publisher
Nature Publishing Group
Start Page
142
End Page
153
Journal / Book Title
Molecular Therapy : Nucleic Acids
Volume
23
Copyright Statement
© 2020 The Author(s).This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Sponsor
British Heart Foundation
Royal Embassy Of Saudi Arabia
Grant Number
PG/16/4/31849
NC223
Subjects
0601 Biochemistry and Cell Biology
1103 Clinical Sciences
Publication Status
Published
Date Publish Online
2020-11-04