Lovastatin-induced decrease of intracellular cholesterol level attenuates fibroblast-to-myofibroblast transition in bronchial fibroblasts derived from asthmatic patients
Marta Michalik , Ewelina Soczek , Milena Kosińska , Monika Rak , Katarzyna Anna Wójcik , Sławomir Lasota , Małgorzata Pierzchalska , Jarosław Czyż , Zbigniew Madeja
AbstractChronic inflammation of the airways and structural changes in the bronchial wall are basic hallmarks of asthma. Human bronchial fibroblasts derived from patients with diagnosed asthma display in vitro predestination towards TGF-β-induced fibroblast-to-myofibroblast transition (FMT), a key event in the bronchial wall remodelling. Statins inhibit 3-hydroxymethyl-3-glutaryl coenzyme A reductase, a key enzyme in the cholesterol synthesis pathway and are widely used as antilipidemic drugs. The pleiotropic anti-inflammatory effects of statins, independent of their cholesterol-lowering capacity, are also well established. Since commonly used anti-asthmatic drugs do not reverse the structural remodelling of the airways and statins have tentative anti-asthmatic activity, we have studied the effect of lovastatin on FMT in populations of human bronchial fibroblasts derived from asthmatic patients. We demonstrate that the intensity of FMT induced by TGF-β1 was strongly and dose-dependently attenuated by lovastatin. Furthermore, we show that neither the suppression of prenylation of signalling proteins nor the effect on reactive oxygen species formation are important for lovastatin-induced inhibition of myofibroblast differentiation. On the other hand, we show that a squalene synthase inhibitor, zaragozic acid A, reduced the TGF-β1-induced FMT to an extent comparable to lovastatin effect. Additionally we demonstrate that in bronchial fibroblast populations, both inhibitors (lovastatin and zaragozic acid A) attenuate the TGF-β1-induced Smad2 nuclear translocation in a manner dependent on intracellular cholesterol level. Our data suggest that statins can directly, by decrease of intracellular cholesterol level, affect basic cell signalling events crucial for asthmatic processes and potentially prevent perilous bronchial wall remodelling associated with intensive myofibroblast formation.
|Journal series||European Journal of Pharmacology, ISSN 0014-2999, (A 25 pkt)|
|Publication size in sheets||0.5|
|Keywords in English||Lovastatin, Cholesterol, Asthma, Human bronchialfibroblasts, Fibroblast-to-myofibroblast transition, Transforming growthfactor b|
|Score|| = 30.0, 26-07-2017, ArticleFromJournal|
= 30.0, 26-07-2017, ArticleFromJournal
|Publication indicators||= 18|
|Finansowanie||The described experiments were financially supported by grant from the Polish Ministry of Science and Higher Education (N N301 050236) and, in part, by the Polish National Science Centre (2011/01/B/NZ3/00004). The Faculty of Biochemistry, Biophysics and Biotechnology of the Jagiellonian University is a beneficary of structural funds from the European Union (Grants no: UDA-POIG.01.03.01-14-036/09-00; POIG.02.02.00-12-064/08 and POIG 01.02-000-109/99)|
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