MFN2-dependent mitochondrial dysfunction contributes to Relm-ß-induced pulmonary arterial hypertension via USP18/Twist1/miR-214 pathway.
Eur J Pharmacol
; 980: 176828, 2024 Oct 05.
Article
em En
| MEDLINE
| ID: mdl-39094924
ABSTRACT
Induction of resistin-like molecule ß (Relm-ß) and mitofusin 2 (MFN2) mediated aberrant mitochondrial fission have been found to be involved in the pathogenesis of pulmonary arterial hypertension (PAH). However, the molecular mechanisms underlying Relm-ß regulation of MFN2 therefore mitochondrial fission remain unclear. This study aims to address these issues. Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. The results showed that Relm-ß promoted cells proliferation in PASMCs, this was accompanied with the upregulation of USP18, Twist1 and miR-214, and downregulation of MFN2. We found that Relm-ß increased USP18 expression which in turn raised Twist1 by suppressing its proteasome degradation. Elevation of Twist1 increased miR-214 expression and then reduced MFN2 expression and mitochondrial fragmentation leading to PASMCs proliferation. In vivo study, we confirmed that Relm-ß was elevated in MCT-induced PAH rat model, and USP18/Twist1/miR-214/MFN2 axis was altered similar as in vitro. Targeting this cascade by Relm-ß receptor inhibitor Calhex231, proteasome inhibitor MG-132, Twist1 inhibitor Harmine or miR-214 antagomiR prevented the development of pulmonary vascular remodeling and therefore PAH in MCT-treated rats. In conclusion, we demonstrate that Relm-ß promotes PASMCs proliferation and vascular remodeling by activating USP18/Twist1/miR-214 dependent MFN2 reduction and mitochondrial fission, suggesting that this signaling pathway might be a promising target for management of PAH.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Ratos Sprague-Dawley
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MicroRNAs
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Ubiquitina Tiolesterase
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Proliferação de Células
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Proteína 1 Relacionada a Twist
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GTP Fosfo-Hidrolases
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Mitocôndrias
Idioma:
En
Revista:
Eur J Pharmacol
Ano de publicação:
2024
Tipo de documento:
Article