Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension

Sindi, Hebah A, Russomanno, Giusy ORCID: 0000-0002-3378-5524, Satta, Sandro, Abdul-Salam, Vahitha B, Jo, Kyeong Beom, Qazi-Chaudhry, Basma, Ainscough, Alexander J, Szulcek, Robert, Bogaard, Harm Jan, Morgan, Claire C
et al (show 8 more authors) (2020) Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension. NATURE COMMUNICATIONS, 11 (1). 1185-.

[img] Text
Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension.pdf - Published version

Download (3MB) | Preview


Pulmonary arterial hypertension (PAH) is a severe disorder of lung vasculature that causes right heart failure. Homoeostatic 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 remodelling and that their actions are mediated by Notch4 and ETS1 and other key regulators of vascular homoeostasis. 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 signalling 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.

Item Type: Article
Uncontrolled Keywords: Lung, Pulmonary Artery, Endothelial Cells, Animals, Humans, Mice, Disease Models, Animal, Disease Progression, MicroRNAs, Signal Transduction, Cell Proliferation, Gene Expression Regulation, Mutation, Missense, Adult, Aged, Middle Aged, Female, Male, Kruppel-Like Transcription Factors, Exosomes, Young Adult, Primary Cell Culture, Genetic Therapy, Vascular Remodeling, Pulmonary Arterial Hypertension
Depositing User: Symplectic Admin
Date Deposited: 06 May 2020 09:43
Last Modified: 18 Jan 2023 23:52
DOI: 10.1038/s41467-020-14966-x
Related URLs: