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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| Hauptverfasser: | , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
04 March 2020
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| In: |
Nature Communications
Year: 2020, Jahrgang: 11 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-14966-x |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 520 | |a 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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