Monocyte Chemotactic Protein 1 Amplifies Serotonin-Induced Vascular Smooth Muscle Cell Proliferation
- 11 July 2001
- journal article
- Published by S. Karger AG in Journal of Vascular Research
- Vol. 38 (4) , 341-349
- https://doi.org/10.1159/000051065
Abstract
Monocyte chemotactic protein 1 (MCP-1), which is synthesized by vascular cells, is a chemoattractant for monocytes and has been implicated in a wide range of acute and chronic inflammatory processes characterized by monocyte infiltration, including atherosclerosis. However, it is unclear whether MCP-1 is able to modulate vascular smooth muscle cell (VSMC) proliferation. We assessed the effect of MCP-1 on VSMC proliferation and its interaction with serotonin (5-HT), a mitogen for VSMCs. Growth-arrested VSMCs were stimulated with different concentrations of MCP-1 (25–200 ng/ml) and 5-HT (5 and 50 µM) in serum-free medium. DNA synthesis in VSMCs was measured by [3H]thymidine incorporation. 5-HT at concentrations of 5 and 50 µM significantly stimulated DNA synthesis by 1.8- and 2.1-fold over the control value, respectively (p < 0.0001). However, MCP-1 at the concentrations tested did not have any significant effect on DNA synthesis. Even though MCP-1 (50 ng/ml) by itself is not mitogenic, when added to 5-HT, it significantly amplified the mitogenic effect of 5-HT compared with that of 5-HT alone (p < 0.0001). The 5-HT2A receptor antagonist sarpogrelate (10 µM) and its major metabolite M-1 (0.1 µM), pertussis toxin (10 ng/ml), Src family protein tyrosine kinase (PTK) inhibitor PP2 (1 µM), protein kinase C (PKC) inhibitor Ro31-8220 (0.1 µM) and mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 (10 µM) significantly inhibited the mitogenic effect of 5-HT and its interaction with MCP-1. Anti-MCP-1 antibody (2 µg/ml) and the Janus kinase 2 (JAK2) inhibitor AG490 (10 µM) significantly inhibited the interaction of MCP-1 with 5-HT. Further, the amplified mitogenic effect of 5-HT with MCP-1 was completely reversed by the combined use of sarpogrelate with anti-MCP-1 antibody. Our results suggest that MCP-1 amplifies the mitogenic effect of 5-HT on VSMCs. The mitogenic effect of 5-HT may be mediated by the G protein-Src family PTK-PKC-MAPK pathway. The activation of the JAK2/signal transducer and activator of transcription 3 pathway by MCP-1 in addition to the MAPK pathway by 5-HT may explain the potentiating effect of MCP-1 on 5-HT-induced mitogenesis.Keywords
This publication has 10 references indexed in Scilit:
- Src and Cas Mediate JNK Activation but Not ERK1/2 and p38 Kinases by Reactive Oxygen SpeciesJournal of Biological Chemistry, 2000
- Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2Proceedings of the National Academy of Sciences, 1998
- Tissue Factor Is Induced by Monocyte Chemoattractant Protein-1 in Human Aortic Smooth Muscle and THP-1 CellsJournal of Biological Chemistry, 1997
- Discovery of a Novel, Potent, and Src Family-selective Tyrosine Kinase InhibitorJournal of Biological Chemistry, 1996
- Histamine Antagonizes Serotonin and Growth Factor-induced Mitogen-activated Protein Kinase Activation in Bovine Tracheal Smooth Muscle CellsPublished by Elsevier ,1995
- The PKC-Inhibitor RO 31-8220 Selectively Suppresses PMA- and Diacylglycerol-Induced Fluid Pinocytosis and Actin Polymerization in PMNSBiochemical and Biophysical Research Communications, 1993
- Selective Inhibition of the Growth of ras-Transformed Human Bronchial Epithelial Cells by Emodin, a Protein-Tyrosine Kinase InhibitorBiochemical and Biophysical Research Communications, 1993
- Detection of monocyte chemoattractant protein-1 in human atherosclerotic lesions by an anti-monocyte chemoattractant protein-1 monoclonal antibodyHuman Pathology, 1993
- The pathogenesis of atherosclerosis: a perspective for the 1990sNature, 1993
- Tyrphostins—Potential antiproliferative agents and novel molecular toolsBiochemical Pharmacology, 1990