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Therapeutic potential of KLF2 induced exosomal microRNAs in pulmonary hypertension

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Title: Therapeutic potential of KLF2 induced exosomal microRNAs in pulmonary hypertension
Authors: Sindi, H
Russomanno, G
Satta, S
Abdul Saalam, V
Kyeong Beom, J
Qazi-Chaudhry, B
Ainscough, A
Szulcek, R
Bogaard, HJ
Morgan, C
Pullamsetti, S
Alzaydi, M
Rhodes, C
Piva, R
Eichstaedt, C
Grünig, E
Wilkins, M
Wojciak-Stothard, B
Item Type: Journal Article
Abstract: Pulmonary arterial hypertension (PAH) is a severe disorder of lung vasculature that causes right heart failure. Homeostatic effects of flow-activated transcription factor Krüppel-like factor 2 (KLF2) are compromised in PAH. Here we show that KLF2-induced exosomal microRNAs, miR-181a-5p and miR-324-5p act together to attenuate pulmonary vascular remodeling and that their actions are mediated by Notch4 and ETS1 and other key regulators of vascular homeostasis. Expressions of KLF2, miR-181a-5p and miR-324-5p are reduced, while levels of their target genes are elevated in pre-clinical PAH, idiopathic PAH and heritable PAH with missense p.H288Y KLF2 mutation. Therapeutic supplementation of miR-181a-5p and miR-324-5p reduces proliferative and angiogenic responses in patient-derived cells and attenuates disease progression in PAH mice. This study shows that reduced KLF2 signaling is a common feature of human PAH and highlights the potential therapeutic role of KLF2-regulated exosomal miRNAs in PAH and other diseases associated with vascular remodelling.
Editors: Piccoli, M-T
Issue Date: 4-Mar-2020
Date of Acceptance: 10-Feb-2020
URI: http://hdl.handle.net/10044/1/77873
DOI: 10.1038/s41467-020-14966-x
ISSN: 2041-1723
Publisher: Nature Research (part of Springer Nature)
Journal / Book Title: Nature Communications
Volume: 11
Copyright Statement: © 2020 Crown. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Saudi Arabian Cultural Bureau
British Heart Foundation
British Heart Foundation
Royal Embassy Of Saudi Arabia
King Abdulaziz City for Science and Technology (KACST)
Funder's Grant Number: HEBAH ADEL A SINDI - K1409
PG/16/4/31849
FS/17/64/33476
NC223
120/16281
Publication Status: Published
Article Number: 1185
Online Publication Date: 2020-03-04
Appears in Collections:National Heart and Lung Institute