Krüppel-like factor 2-induced microRNAs: implications for treatment of pulmonary hypertension.

Hebah Sindi, Giusy Russomanno, Kyeong Beom Jo, Vahitha B. AbdulSalam, Basma Qazi Chaudhry, Alexander J. Ainscough, Robert Szulcek, Harm Jan Bogaard, Claire C. Morgan, Soni Pullamsetti, Mai Alzaydi, Christopher J. Rhodes, Christina A. Eichstaedt, Ekkehard Grünig, Martin R. Wilkins, and Beata Wojciak-Stothard

Apr 10, 2019
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Received Date: 22nd March 19

Flow-activated transcription factor Krüppel-like factor 2 (KLF2) induces intercellular exchange of microRNAs to protect vascular homeostasis. Pulmonary arterial hypertension (PAH) is characterised by endothelial damage followed by progressive vascular remodelling. We aimed to identify KLF2-induced exosomal microRNAs of potential therapeutic significance.

We describe a subset of disease-relevant exosomal microRNAs released by KLF2-overexpressing and flow-stimulated human pulmonary endothelial cells. Of these, only miR-181a-5p and miR-324-5p showed synergistic endothelium-protective effects in vitro and in vivo. Dysregulation of KLF2-regulated microRNAs and their gene targets involved in vascular remodelling was seen in cells and lung tissues from idiopathic and heritable PAH patients with disabling KLF2 mutation and pulmonary hypertensive mice. miR-181a-5p and miR-324-5p prevented development of pulmonary hypertension in Sugen/hypoxia mice, while silencing of their target genes ETS-1 and NOTCH4 attenuated proliferative and angiogenic responses in cells from idiopathic PAH.

This study highlights potential therapeutic role of KLF2-induced exosomal microRNAs in PAH.

Read in full at bioRxiv.

This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature