title: Monocyte chemotactic protein-3 induces human coronary smooth muscle cell proliferation.
abstract: 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 μM), 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 μM) and LY-294002 (5μM), selective inhibitors of ERK 1/2 and PI3K activation, respectively. We found no relationship between MCP-3-induced CASMC proliferation and nuclear factor-κB activation. Moreover, we found that tumor necrosis factor-α (TNF-α, 30 ng/mL) and interleukin-1β (IL-1β, 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.
authors.affiliation: Department of Experimental Pharmacology, University of Naples Federico II, Via Domenico Montesano, 49, 80131 Naples, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Maddaluno
authors.forename: Mariavittoria
authors.initials: M
authors.lastname: Di Lauro
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Pascale
authors.forename: Rita
authors.initials: R
authors.lastname: Santamaria
authors.forename: Angelo
authors.initials: A
authors.lastname: Guglielmotti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Grassia
authors.forename: Armando
authors.initials: A
authors.lastname: Ialenti
mesh_terms: D001973:Bromodeoxyuridine / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation; D054410:Chemokine CCL7 / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D003331:Coronary Vessels / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D054390:Receptors, CCR2 / Q000378:metabolism; D013997:Time Factors
chemical_list: D002070:Butadienes; D054410:Chemokine CCL7; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D016328:NF-kappa B; D009570:Nitriles; D054390:Receptors, CCR2; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D048049:Extracellular Signal-Regulated MAP Kinases; D001973:Bromodeoxyuridine