Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension

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 C. Morgan, Soni S. Pullamsetti, Mai M. Alzaydi, Christopher J. Rhodes, Roberto Piva, Christina A. Eichstaedt, Ekkehard Grünig, Martin R. Wilkins, Beata Wojciak-Stothard

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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.

Original languageEnglish
Article number1185
JournalNature communications
Issue number1
Publication statusPublished - 1 Dec 2020

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