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Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension

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-32...

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Main Authors: Sindi, Hebah A. (Author) , Russomanno, Giusy (Author) , Satta, Sandro (Author) , Abdul-Salam, Vahitha B. (Author) , Jo, Kyeong Beom (Author) , Qazi-Chaudhry, Basma (Author) , Ainscough, Alexander J. (Author) , Szulcek, Robert (Author) , Jan Bogaard, Harm (Author) , Morgan, Claire C. (Author) , Pullamsetti, Soni S. (Author) , Alzaydi, Mai M. (Author) , Rhodes, Christopher J. (Author) , Piva, Roberto (Author) , Eichstaedt, Christina (Author) , Grünig, Ekkehard (Author) , Wilkins, Martin R. (Author) , Wojciak-Stothard, Beata (Author)
Format: Article (Journal)
Language:English
Published: 04 March 2020
In: Nature Communications
Year: 2020, Volume: 11
ISSN:2041-1723
DOI:10.1038/s41467-020-14966-x
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-020-14966-x
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-020-14966-x
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Author Notes: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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Summary: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 Description:Gesehen am 17.09.2020
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-020-14966-x

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