Antidepressants induce profibrotic responses via the lysophosphatidic acid receptor LPA 1 .

Autor: Olianas MC; Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. Electronic address: molianas@unica.it., Dedoni S; Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy., Onali P; Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2020 Apr 15; Vol. 873, pp. 172963. Date of Electronic Publication: 2020 Jan 30.
DOI: 10.1016/j.ejphar.2020.172963
Abstrakt: Preclinical and clinical studies have indicated that antidepressants can promote inflammation and fibrogenesis, particularly in the lung, by mechanisms not fully elucidated. We have previously shown that different classes of antidepressants can activate the lysophosphatidic acid (LPA) receptor LPA 1 , a major pathogenetic mediator of tissue fibrosis. The aim of the present study was to investigate whether in cultured human dermal and lung fibroblasts antidepressants could trigger LPA 1 -mediated profibrotic responses. In both cell types amitriptyline, clomipramine and mianserin mimicked the ability of LPA to induce the phosphorylation/activation of extracellular signal -regulated kinases 1 and 2 (ERK1/2), which was blocked by the selective LPA 1 receptor antagonist AM966 and the LPA 1/3 antagonist Ki16425. Antidepressant-induced ERK1/2 stimulation was absent in fibroblasts stably depleted of LPA 1 by short hairpin RNA transfection and was prevented by pertussis toxin, an uncoupler of receptors from Gi/o proteins. Like LPA, antidepressants stimulated fibroblasts proliferation and this effect was blocked by either AM966 or the MEK1/2 inhibitor PD98059. Moreover, by acting through LPA 1 antidepressants induced the expression of α-smooth muscle actin (α-SMA), a marker of myofibroblast differentiation, and caused an ERK1/2-dependent increase in the cellular levels of transforming growth factor-β (TGF-β)1, a potent fibrogenic cytokine. Pharmacological blockade of TGF-β receptor type 1 prevented antidepressant- and LPA-induced α-SMA expression. These data indicate that in human dermal and lung fibroblasts different antidepressants can induce proliferative and differentiating responses by activating the LPA 1 receptor coupled to ERK1/2 signalling and suggest that this property may contribute to the promotion of tissue fibrosis by these drugs.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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