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

Nature Communications
Hebah A SindiBeata Wojciak-Stothard

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.

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Citations

May 8, 2020·International Journal of Molecular Sciences·Susana Carregal-RomeroJesús Ruíz-Cabello
Oct 20, 2020·Frontiers in Oncology·Tao FanJie He
Oct 23, 2020·Journal of Cellular and Molecular Medicine·Zhaohua ZhangYun Luan
Nov 21, 2020·The EMBO Journal·Eunkyoung ShinJeehyeon Bae
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Dec 19, 2020·Molecular Therapy. Nucleic Acids·Giusy RussomannoBeata Wojciak-Stothard
Jan 30, 2021·Frontiers in Cell and Developmental Biology·Dongdong ZhengKexiang Liu
Apr 12, 2021·The International Journal of Biochemistry & Cell Biology·Salina NicoleauBeata Wojciak-Stothard
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Jun 24, 2021·International Journal of Stem Cells·Zhou JiQing Tong
Jun 25, 2021·American Journal of Respiratory Cell and Molecular Biology·Camilla Margaroli, Derek Russell

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Methods Mentioned

BETA
PCR
transfection
confocal microscopy
genetic modification
FCS
density gradient centrifugation
Protein Assay
electrophoresis
Assay
PCRs

Software Mentioned

ImageJ
bcl2fastq2 Conversion
Roche LC
Ismatec
STRING
FastQC
Image J
CellQuest Pro
DESeq2
Panther Pathway Analysis ( IPA

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