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RETRACTED ARTICLE: Thrombin stimulates VSMC proliferation through an EGFR-dependent pathway: involvement of MMP-2

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This article was retracted on 25 April 2024

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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.

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Abbreviations

ADAM:

A disintegrin and metalloproteinases

ANG II:

Angiotensin II

AG:

Reversible epidermal growth factor receptor tyrosine kinase inhibitor—AG1478

BrdU:

Thymidine analog, 5 bromo 2 deoxyuridine

DMEM:

Dulbecco’s modified Eagle’s medium

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

ERK1/2:

Extracellular signal regulated kinase 1/2

FCS:

Fetal calf serum

GM:

Hydroxamic acid class of reversible metallopeptidase inhibitors—GM6001

GPCR:

G protein coupled receptor

HB-EGF:

Heparin binding epidermal growth-factor like growth factor

HEPES buffer:

(4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid)—a zwitterionic organic chemical buffering agent

IC50 :

Concentration of an inhibitor where the response (or binding) is reduced by half

MAPK:

Mitogen activated protein kinases

MEK:

MAPKK, MAPK kinase

MMP:

Matrix metalloproteinases

MMP-2:

Matrix metalloproteinase 2

MP:

Metalloproteinases

PD:

Irreversible inhibitors of the epidermal growth factor receptor—PD 169540

PDGF:

Platelet-derived growth factor

PHEN:

o-Phenantroline, an inhibitor of total MP

PKC:

Protein kinase C

PKCδ:

Protein kinase C delta

pro HB-EGF:

pro Heparin binding epidermal growth factor-like growth factor

Raf:

Rapidly accelerated fibrosarcoma kinase

SDS:

Sodium dodecyl sulphate

SDS-PAGE:

SDS-polyacrylamide gel electrophoresis

SI-II:

MMP-2 specific inhibitor

VSMC:

Vascular smooth muscle cells

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Acknowledgments

This work was supported from the grant founded by CNRS and University Pierre and Marie Curie (to P.M.), from the Grant No. 173033 to (E.R.I.) funded by the Ministry of Science, Republic of Serbia, and by the grant 337-00-359/2005-01/16 founded by the “Pavle Savić”, and Republic of France, Ministry of Foreign Affairs (to P.M. and E.R.I). The authors are very grateful to Dr. Mirjana Macvanin for her helpful suggestions and constructive comments and great help in writing this manuscript.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Chemistry, University of Belgrade, Studentski trg 16, 11000, Belgrade, Serbia

    Katarina Smiljanic

  2. Laboratory for Molecular Genetics and Radiobiology, Vinca Institute of Nuclear Sciences, University of Belgrade, P.O. Box 522, Mike Petrovica Alasa 12-14, 11001, Belgrade, Serbia

    Milan Obradovic, Aleksandra Jovanovic, Branislava Dobutovic & Esma R. Isenovic

  3. Faculty of Biology, University of Belgrade, Studentski trg 16, 11000, Belgrade, Serbia

    Jelena Djordjevic

  4. Faculty of Stomatology in Pancevo, University Business Academy, Novi Sad, Serbia

    Danimir Jevremovic

  5. Faculté de Médecine Pitié-Salpétrière, INSERM UMR 956 and Univ P & M Curie, 91 Bd l’Hôpital, 75634, Paris Cedex 13, France

    Pierre Marche

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  1. Katarina Smiljanic
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This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1007/s11010-024-05016-x

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Smiljanic, K., Obradovic, M., Jovanovic, A. et al. RETRACTED ARTICLE: Thrombin stimulates VSMC proliferation through an EGFR-dependent pathway: involvement of MMP-2. Mol Cell Biochem 396, 147–160 (2014). https://doi.org/10.1007/s11010-014-2151-y

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