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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 |
Appears in Collections: | Journal Article |
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