Monocyte chemotactic protein-3 induces human coronary smooth muscle cell proliferation.

摘要

Monocyte chemotactic protein-3 (MCP-3), also known as CCL7, belongs to the monocyte chemotactic protein (MCP) subfamily of the CC chemokines that includes MCP-1/CCL2, MCP-2/CCL8, MCP-4/CCL13, and MCP-5/CCL12. Few studies have examined the role of MCP-3 in vascular pathologies such as atherosclerosis and restenosis in which smooth muscle cell (SMC) proliferation plays an important role. In this study, we investigated the effect of MCP-3 on human coronary artery smooth muscle cell (CASMC) proliferation. MCP-3 induced concentration-dependent CASMC proliferation with the maximum stimulatory effect at 0.3 ng/mL (about 50% vs unstimulated cells) assessed by bromodeoxyuridine (BrdU) uptake and direct cell counting. Anti-MCP-3 antibody (20 ng/mL) completely inhibited cell proliferation, demonstrating the specificity of the proliferative effect of MCP-3. Moreover, the MCP-3-induced CASMC proliferation was blocked by RS 102895 (0.06-6 muM), a specific antagonist of chemokine receptor 2 (CCR2). The mitogenic effect of MCP-3 appeared to be dependent on ERK1/2 MAPK and PI3K signaling pathway activation, as demonstrated by the reduction of MCP-3-induced CASMC proliferation observed after the treatment of cells with U0126 (1 muM) and LY-294002 (5muM), selective inhibitors of ERK 1/2 and PI3K activation, respectively. We found no relationship between MCP-3-induced CASMC proliferation and nuclear factor-kappaB activation. Moreover, we found that tumor necrosis factor-alpha (TNF-alpha, 30 ng/mL) and interleukin-1beta (IL-1beta, 1 ng/mL) both induced time-dependent increase of MCP-3 production by CASMCs, which was reduced by the anti-MCP-3 antibody (20 ng/mL), suggesting that the mitogenic effect of these stimuli is due, at least in part, to MCP-3. In conclusion, our results demonstrate that MCP-3 is produced by human CASMCs and directly induces CASMC proliferation in vitro, suggesting a potential role for this chemokine in vascular pathology.