Prostacyclin Receptor Agonists Induce DUSP1 to Inhibit Pulmonary Artery Smooth Muscle Cell Proliferation
| Autor: | Hidekazu Maruyama, Satoshi Sakai, Laurence Dewachter, Céline Dewachter, Benoit Rondelet, Robert Naeije, Masaki Ieda |
|---|---|
| Přispěvatelé: | UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de chirurgie cardio-vasculaire et thoracique |
| Rok vydání: | 2022 |
| Předmět: |
IP receptor
History Smooth muscle cells Polymers and Plastics General Medicine General Pharmacology Toxicology and Pharmaceutics Business and International Management Pulmonary arterial hypertension MAPK General Biochemistry Genetics and Molecular Biology DUSP1 Industrial and Manufacturing Engineering |
| Zdroj: | Life sciences, Vol. 315, p. 121372 (2023) |
| ISSN: | 1556-5068 |
| DOI: | 10.2139/ssrn.4249928 |
| Popis: | Upregulated p38 signaling is implicated in the accelerated proliferation of pulmonary artery smooth muscle cells (PA-SMCs) and the pathogenesis of pulmonary artery remodeling observed in pulmonary arterial hypertension (PAH). Previously, we reported that after endothelin-1 (ET-1) pretreatment, bone morphogenetic protein 2 (BMP2) activates p38 signaling and accelerates PA-SMC proliferation. The activity of p38 signaling is tightly regulated by the inactivation of dual-specificity phosphatase 1 (DUSP1). Activated p38 induces DUSP1 expression, forming a negative feedback loop. Prostacyclin IP receptor agonists (prostacyclin and selexipag) are used to treat PAH. In this study, we aimed to verify whether IP receptor agonists affect DUSP1 expression and accelerate the proliferation of PA-SMCs. PA-SMCs were treated with BMP2, ET-1, prostacyclin, and MRE-269, an active metabolite of selexipag, either alone or in combination. We quantified mRNA expressions using real-time quantitative polymerase chain reaction. Pulmonary artery specimens and PA-SMCs were obtained during lung transplantation in patients with PAH. Both prostacyclin and MRE-269 increased DUSP1 expression. Combined treatment with BMP2 and ET-1 induced cyclin D1 and DUSP1 expression and increased PA-SMC proliferation. MRE-269 attenuated BMP2/ET-1-induced cell proliferation. ET-1 increased DUSP1 expression in PA-SMCs from control patients but not in PA-SMCs from patients with PAH. This study showed that the p38/DUSP1 negative feedback loop is impaired in PAH, contributing to unregulated p38 activation and PA-SMC hyperplasia. IP receptor agonist MRE-269 increases DUSP1 expression and inhibit p38-mediated PA-SMC proliferation. Future elucidation of the detailed mechanism underlying reduced DUSP1 expression would be informative for PAH treatment. |
| Databáze: | OpenAIRE |
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