ArticleArthritis research & therapy2015
Macitentan inhibits the transforming growth factor-β profibrotic action, blocking the signaling mediated by the ETR/TβRI complex in systemic sclerosis dermal fibroblasts.
Article in Arthritis research & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 24 citations in OpenAlex.
- Sustained benefit from combined plasmapheresis and allogeneic mesenchymal stem cells transplantation therapy in systemic sclerosis.Arthritis research & therapy · 2017Trial
- Beyond Reperfusion: Early Molecular Drivers and Therapeutic Opportunities in Acute Post-Infarction Cardiac Fibrosis.International journal of molecular sciences · 2026Review
- Pulmonary arterial hypertension drugs can partially restore altered angiogenic capacities inPulmonary circulation · 2023Article
- The Pathogenesis of Systemic Sclerosis: The Origin of Fibrosis and Interlink with Vasculopathy and Autoimmunity.International journal of molecular sciences · 2023Review
- MiRNAs in Systemic Sclerosis Patients with Pulmonary Arterial Hypertension: Markers and Effectors.Biomedicines · 2022Article
- Endothelial-to-mesenchymal transition in systemic sclerosis.Clinical and experimental immunology · 2021Review
- Mesenchymal stem cells of Systemic Sclerosis patients, derived from different sources, show a profibrotic microRNA profiling.Scientific reports · 2019Article
- Article
- Blocking CD248 molecules in perivascular stromal cells of patients with systemic sclerosis strongly inhibits their differentiation toward myofibroblasts and proliferation: a new potential target for antifibrotic therapy.Arthritis research & therapy · 2018Article
- Effects of selexipag and its active metabolite in contrasting the profibrotic myofibroblast activity in cultured scleroderma skin fibroblasts.Arthritis research & therapy · 2018Article
- Angiogenesis Dysregulation in the Pathogenesis of Systemic Sclerosis.BioMed research international · 2017Review
- Bosentan and macitentan prevent the endothelial-to-mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study.Arthritis research & therapy · 2016Article
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11 authors at 1 institution in 1 country.
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Abstract
introductionSystemic sclerosis (SSc) is a complex and not fully understood autoimmune disease associated with fibrosis of multiple organs. The main effector cells, the myofibroblasts, are collagen-producing cells derived from the activation of resting fibroblasts. This process is regulated by a complex repertoire of profibrotic cytokines, and among them transforming growth factor beta (TGF-β) and endothelin-1 (ET-1) play a major role. In this paper we show that TGF-β and ET-1 receptors co-operate in myofibroblast activation, and macitentan, an ET-1 receptor antagonist binding ET-1 receptors, might interfere with both TGF-β and ET-1 pathways, preventing myofibroblast differentiation.
methodsFibroblasts isolated from healthy controls and SSc patients were treated with TGF-β and ET-1 and successively analyzed for alpha smooth muscle actin (α-SMA) and collagen (Col1A1) expression and for the Sma and Mad Related (SMAD) phosphorylation. We further tested the ability of macitentan to interfere with these process. Furthermore, we silenced ET-1 and endothelin-1 receptor A expression and evaluated the formation of an ET-1/TGF-β receptor complex by immunoprecitation assay.
resultsWe showed myofibroblast activation in SSc fibroblasts assessing the expression of α-SMA and Col1A1, after stimulation with TGF-β and ET-1. Macitentan interfered with both ET-1- and TGF-β-induced fibroblast activation. To explain this unexpected inhibitory effect of macitentan on TGF-β activity, we silenced ET-1 expression on SSc fibroblasts and co-immunoprecipitated these two receptors, showing the formation of an ET-1/TGF-β receptor complex.
conclusionsDuring SSc, ET-1 produced by activated endothelia contributes to myofibroblast activation using TGF-β machinery via an ET-1/TGF-β receptor complex. Macitentan interferes with the profibrotic action of TGF-β, blocking the ET-1 receptor portion of the ET-1/TGF-β receptor complex.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.