Stimulation Of Alpha7 Nicotinic Acetylcholine Receptor Attenuates Nicotine-induced Upregulation Of MMP-9, MMP-2, MCP-1 And RANTES In Macrophages And Aortic Smooth Muscle Cells

Backgrouds: Inflammation and matrix degration in the vasculature are crucial for abdominal aortic aneurysm(AAA).Macrophages and aortic smooth muscle cells are the most important cells,which can induce the development of AAA by secreting matrix metalloproteinase(MMP)and inflammatory factors.Smoking is a very strong modifiable risk factor for AAA.The cholinergic anti-inflammatory pathway,composed of alpha7 nicotine acetylcholine receptor(?7-nAChR),the efferent vagus nerve and the neurotransmitter acetylcholine,had been demonstrated attenuation of inflammation and improvement of inflammatory diseases.Objective: This study aimed to determine whether PNU-282987,a selective ?7-nAChR agonist,affected activities of MMPs and inflammatory cytokines in nicotinetreatment macrophage(RAW264.7 cell)and aortic smooth muscle cell(MOVAS cell)and to assess the underlying molecular mechanisms.Methods and Results: Firstly,RAW264.7 and MOVAS cells were treated with 10ng/ml nicotine for 0,10,20,30,60 and 120 min.Then,RAW264.7 and MOVAS cells were treated with nicotine for 30 min at the concentrations of 0,1,10 and 100ng/ml.Nicotine markedly stimulated the phosphorylation of extracellular signalregulated kinase1/2(ERK1/2)and c-Jun in RAW264.7 cells.Pretreatment with U0126,a high selective inhibitor of MEK1/2,significantly suppressed phosphorylation of ERK1/2,and further attenuated nicotine-induced activation of c-Jun and upregulation of MMP-2,MMP-9,monocyte chemotactic protein(MCP)-1 and regulated upon activation normal T cell expressed and secreted(RANTES).Similarly,nicotine treatment also increased phosphorylation of c-Jun and expressions of MMP-2,MMP-9,MCP-1 and RANTES in MOVAS cells.When cells were pretreated with PNU-282987,nicotine-induced activations of ERK1/2 and c-Jun in macrophage and c-Jun in aortic smooth muscle cell were effectively inhibited.Furthermore,nicotine-induced secretions of MMP-2,MMP-9,MCP-1 and RANTES were remarkably downregulated.Conclusion: Treatment with ?7-nAChR agonist inhibits nicotine-induced upregulation of MMP and inflammatory cytokines through modulating ERK1/2/AP-1(c-Jun)signaling in macrophage and AP-1(c-Jun)in aortic smooth muscle cell,providing a new therapeutic for AAA.