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 Bogaard, Claire C. Morgan, Soni S. Pullamsetti, Mai M. Alzaydi, Christopher J. Rhodes, Roberto Piva, Christina A. Eichstaedt, Ekkehard Grünig, Martin R. Wilkins and Beata Wojciak-Stothard ()
Additional contact information
Hebah A. Sindi: Imperial College London
Giusy Russomanno: Imperial College London
Sandro Satta: Imperial College London
Vahitha B. Abdul-Salam: Imperial College London
Kyeong Beom Jo: Imperial College London
Basma Qazi-Chaudhry: King’s College London UK
Alexander J. Ainscough: Imperial College London
Robert Szulcek: Amsterdam Cardiovascular Sciences (ACS)
Harm Bogaard: Amsterdam Cardiovascular Sciences (ACS)
Claire C. Morgan: Imperial College London
Soni S. Pullamsetti: Member of the German Center for Lung Research (DZL)
Mai M. Alzaydi: Imperial College London
Christopher J. Rhodes: Imperial College London
Roberto Piva: University of Turin
Christina A. Eichstaedt: German Center for Lung Research (DZL)
Ekkehard Grünig: German Center for Lung Research (DZL)
Martin R. Wilkins: Imperial College London
Beata Wojciak-Stothard: Imperial College London

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14966-x

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