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

Autor:	Russomanno G; National Heart and Lung Institute, Imperial College London, London, UK.; Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK., Jo KB; National Heart and Lung Institute, Imperial College London, London, UK., Abdul-Salam VB; National Heart and Lung Institute, Imperial College London, London, UK.; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Morgan C; National Heart and Lung Institute, Imperial College London, London, UK., Endruschat J; Silence Therapeutics GmbH, Berlin, Germany., Schaeper U; Silence Therapeutics GmbH, Berlin, Germany., Osman AH; National Heart and Lung Institute, Imperial College London, London, UK., Alzaydi MM; National Heart and Lung Institute, Imperial College London, London, UK.; National Center for Biotechnology, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia., Wilkins MR; National Heart and Lung Institute, Imperial College London, London, UK., Wojciak-Stothard B; National Heart and Lung Institute, Imperial College London, London, UK.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2020 Nov 04; Vol. 23, pp. 142-153. Date of Electronic Publication: 2020 Nov 04 (Print Publication: 2021).
DOI:	10.1016/j.omtn.2020.10.042
Abstrakt:	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. Competing Interests: This work involved the collaboration of B.W.-S. with Silence Therapeutics (London, UK), who provided DACC/miRNA preparations. The remaining authors declare no competing interests. (© 2020 The Author(s).)
Databáze:	MEDLINE
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