RESUMO
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.
Assuntos
Terapia Genética/métodos , Fatores de Transcrição Kruppel-Like/metabolismo , MicroRNAs/uso terapêutico , Hipertensão Arterial Pulmonar/terapia , Adulto , Idoso , Animais , Proliferação de Células/genética , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais , Exossomos/genética , Exossomos/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Fatores de Transcrição Kruppel-Like/genética , Pulmão/irrigação sanguínea , Pulmão/citologia , Pulmão/patologia , Masculino , Camundongos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Cultura Primária de Células , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/citologia , Artéria Pulmonar/patologia , Transdução de Sinais/genética , Remodelação Vascular/genética , Adulto JovemRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.