Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension.

Autor: Sindi HA; National Heart and Lung Institute, Imperial College London, London, UK.; University of Jeddah, College of Science, Department of Biology, Jeddah, Saudi Arabia., Russomanno G; National Heart and Lung Institute, Imperial College London, London, UK., Satta S; National Heart and Lung Institute, Imperial College London, London, UK., Abdul-Salam VB; National Heart and Lung Institute, Imperial College London, London, UK., Jo KB; National Heart and Lung Institute, Imperial College London, London, UK., Qazi-Chaudhry B; Department of Physics, King's College London UK, London, UK., Ainscough AJ; National Heart and Lung Institute, Imperial College London, London, UK., Szulcek R; Amsterdam UMC, VU University Medical Center, Department of Pulmonary Diseases, Amsterdam Cardiovascular Sciences (ACS), Amsterdam, The Netherlands., Jan Bogaard H; Amsterdam UMC, VU University Medical Center, Department of Pulmonary Diseases, Amsterdam Cardiovascular Sciences (ACS), Amsterdam, The Netherlands., Morgan CC; National Heart and Lung Institute, Imperial College London, London, UK., Pullamsetti SS; Max Planck Institute for Heart and Lung Research, Department of Lung Development and Remodeling, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany.; Department of Internal MedicineUniversities of Giessen and Marburg Lung Center (UGMLC), Member of the DZL, Justus Liebig University, Giessen, Germany., Alzaydi MM; National Heart and Lung Institute, Imperial College London, London, UK.; National Center for Biotechnology, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia., Rhodes CJ; National Heart and Lung Institute, Imperial College London, London, UK., Piva R; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy., Eichstaedt CA; Centre for Pulmonary Hypertension, Thoraxclinic, Institute for Human Genetics, University of Heidelberg, Translational Lung Research Center (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.; Laboratory of Molecular Genetic Diagnostics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Grünig E; Centre for Pulmonary Hypertension, Thoraxclinic, Institute for Human Genetics, University of Heidelberg, Translational Lung Research Center (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany., Wilkins MR; National Heart and Lung Institute, Imperial College London, London, UK., Wojciak-Stothard B; National Heart and Lung Institute, Imperial College London, London, UK. b.wojciak-stothard@imperial.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Mar 04; Vol. 11 (1), pp. 1185. Date of Electronic Publication: 2020 Mar 04.
DOI: 10.1038/s41467-020-14966-x
Abstrakt: 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.
Databáze: MEDLINE