miR-150-PTPMT1-cardiolipin signaling in pulmonary arterial hypertension.



Russomanno, Giusy ORCID: 0000-0002-3378-5524, Jo, Kyeong Beom, Abdul-Salam, Vahitha B, Morgan, Claire, Endruschat, Jens, Schaeper, Ute, Osman, Ahmed H, Alzaydi, Mai M, Wilkins, Martin R ORCID: 0000-0003-3926-1171 and Wojciak-Stothard, Beata
(2021) miR-150-PTPMT1-cardiolipin signaling in pulmonary arterial hypertension. Molecular therapy. Nucleic acids, 23. 142 - 153.

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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 <i>in vitro</i> and <i>in vivo</i>. 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 <i>in vitro</i> and <i>in vivo</i> were linked with PTPMT1-dependent biosynthesis of mitochondrial phospholipid cardiolipin and reduced expression of pro-apoptotic, pro-inflammatory, and pro-fibrotic genes, including <i>c-MYB</i>, <i>NOTCH3</i>, transforming growth factor β (<i>TGF-β</i>), and <i>Col1a1</i>. 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.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 13 Jan 2021 12:01
Last Modified: 19 Jan 2021 13:10
DOI: 10.1016/j.omtn.2020.10.042
URI: https://livrepository.liverpool.ac.uk/id/eprint/3111818