TY - JOUR
T1 - Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension
AU - Sindi, Hebah A.
AU - Russomanno, Giusy
AU - Satta, Sandro
AU - Abdul-Salam, Vahitha B.
AU - Jo, Kyeong Beom
AU - Qazi-Chaudhry, Basma
AU - Ainscough, Alexander J.
AU - Szulcek, Robert
AU - Jan Bogaard, Harm
AU - Morgan, Claire C.
AU - Pullamsetti, Soni S.
AU - Alzaydi, Mai M.
AU - Rhodes, Christopher J.
AU - Piva, Roberto
AU - Eichstaedt, Christina A.
AU - Grünig, Ekkehard
AU - Wilkins, Martin R.
AU - Wojciak-Stothard, Beata
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85081208223&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-020-14966-x
DO - https://doi.org/10.1038/s41467-020-14966-x
M3 - Article
C2 - 32132543
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1185
ER -