KLF2
ETS1型
小RNA
胚胎血管重塑
癌症研究
肺动脉高压
转录因子
平衡
医学
心力衰竭
肺
错义突变
生物
生物信息学
作者
Hebah A. Sindi,Giusy Russomanno,Sandro Satta,Vahitha B. Abdul-Salam,Kyeong Beom Jo,Basma Qazi-Chaudhry,Alexander J. Ainscough,Robert Szulcek,Harm Jan Bogaard,Claire Morgan,Soni Savai Pullamsetti,Mai M. Alzaydi,Christopher J. Rhodes,Roberto Piva,Christina A. Eichstaedt,Ekkehard Grünig,Martin R. Wilkins,Beata Wojciak-Stothard
标识
DOI:10.1038/s41467-020-14966-x
摘要
Abstract 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.
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