Please use this identifier to cite or link to this item: https://biore.bio.bg.ac.rs/handle/123456789/185
Title: Thrombin stimulates VSMC proliferation through an EGFR-dependent pathway: Involvement of MMP-2
Authors: Smiljanić, Katarina
Obradović, Milan
Jovanović, Aleksandra
Đorđević, Jelena 
Dobutović, Branislava
Jevremović, Danimir
Marche, Pierre
Isenović, Esma
Keywords: Atherosclerosis;EGFR transactivation;Heparin-binding epidermal growth factor like;Matrix metalloproteinase;MMP-2;Pathological VSMC proliferation;Thrombin signaling cascade
Issue Date: 1-Jan-2014
Journal: Molecular and Cellular Biochemistry
Abstract: 
In this study, the role of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK1/2), heparin-binding EGF-like growth factor (HB-EGF), general metalloproteinases, matrix metalloproteinases-2 (MMP-2) in mediating the mitogenic action of thrombin in rat vascular smooth muscle cells (VSMC) was investigated. The incubation of rat VSMC with thrombin (1 U/ml) for 5 min resulted in significant (p < 0.001) increase of ERK1/2 phosphorylation by 8.7 ± 0.9-fold, EGFR phosphorylation by 8.5 ± 1.3-fold (p < 0.001) and DNA synthesis by 3.6 ± 0.4-fold (p < 0.001). Separate 30-min pretreatments with EGFR tyrosine kinase irreversible inhibitor, 10 μM PD169540 (PD), and 20 μM anti-HB-EGF antibody significantly reduced thrombin-stimulated EGFR and ERK1/2 phosphorylation by 81, 72 % and by 48 and 61 %, respectively. Furthermore, the same pretreatments with PD or anti-HB-EGF antibody reduced thrombin-induced VSMC proliferation by 44 and 45 %, respectively. In addition, 30-min pretreatments with 10 μM specific MMP-2 inhibitor significantly reduced thrombin-stimulated phosphorylation of both EGFR and ERK1/2 by 25 %. Moreover, the same pretreatment with MMP-2 inhibitor reduced thrombin-induced VSMC proliferation by 45 %. These results show that the thrombin-induced DNA synthesis correlates with the level of ERK1/2 activation rather than EGFR activation. These results further suggest that thrombin acts through EGFR and ERK 1/2 signaling pathways involving MMP-2 to upregulate proliferation of VSMC.
URI: https://biore.bio.bg.ac.rs/handle/123456789/185
ISSN: 0300-8177
DOI: 10.1007/s11010-014-2151-y
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