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.
Highlights
Pulmonary arterial hypertension (PAH) is a severe disorder of lung vasculature that causes right heart failure
A missense mutation in the transcription factor Krüppel-like factor 2 (KLF2) gene was identified in a family with autosomal heritable pulmonary arterial hypertension (HPAH), suggesting that KLF2 signalling may be compromised in the disease[4]
In order to study the effects of KLF2-induced exosomes, KLF2 was overexpressed in human pulmonary artery endothelial cells (HPAECs) via adenoviral gene transfer
Summary
Pulmonary arterial hypertension (PAH) is a severe disorder of lung vasculature that causes right heart failure. 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. 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. Pulmonary arterial hypertension (PAH) is a severe lung disorder characterised by progressive vascular remodelling and increased vasoconstriction. A missense mutation in the transcription factor Krüppel-like factor 2 (KLF2) gene was identified in a family with autosomal heritable pulmonary arterial hypertension (HPAH), suggesting that KLF2 signalling may be compromised in the disease[4]. Within the blood vessel wall, KLF2 is exclusively expressed in endothelial cells and promotes vascular homoeostasis, counteracting inflammation, vascular leakage, thrombosis and VEGF-induced angiogenesis. Recent studies have shown that miRNAs released by the cells in exosomes, small membrane vesicles of 40–100 nm in diameter, can be taken up and modulate recipient cell responses in the immediate neighbourhood as well as in distant organs and tissues[12,13]
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