title: Visfatin/PBEF/Nampt induces EMMPRIN and MMP-9 production in macrophages via the NAMPT-MAPK (p38, ERK1/2)-NF-κB signaling pathway.
abstract: The adipocytokine visfatin is closely associated with metabolic disorders. This study explored the effects of visfatin on macrophage-induced inflammation in atheroma. The ability of visfatin to enhance extracellular matrix metalloproteinase inducer (EMMPRIN) expression, matrix metalloproteinase-9 (MMP-9) production and enzymatic activity in THP-1 derived macrophages as well as the mechanisms involved were investigated. EMMPRIN and MMP-9 mRNA levels were investigated by RT-PCR. EMMPRIN and MMP-9 protein levels, nuclear factor (NF)-κB -p65 protein levels, peroxisome proliferator-activated receptor γ (PPARγ) protein levels, and mitogen-activated protein kinase (MAPK) phosphorylation were determined by Western blotting. MMP-9 enzymatic activity was assayed by gelatin zymography. Visfatin (50-400 ng/ml) induced EMMPRIN and MMP-9 depending on the dosage used. Visfatin elicited the activation of NF-κB and MAPK (p38, ERK1/2). Exogenous nicotinamide mononucleotide (NMN), the product of nicotinamide phosphoribosyltransferase (NAMPT) activity, mimicked the effects of visfatin on MAPK (p38, ERK1/2)-NF-κB activation and EMMPRIN/MMP-9 induction. Using the p38 inhibitor, SB203580, the ERK1/2 inhibitor PD98059, the NF-κB inhibitor, pyrrolidine dithiocarbamate and the NAMPT inhibitor FK866, we demonstrated that the visfatin pro-inflammatory action was through the NAMPT-MAPK (p38, ERK1/2)-NF-κB pathway. Furthermore, the visfatin pro-inflammatory action was not prevented by insulin receptor blockade or by a PPARγ agonist. Visfatin did not modulate PPARγ expression. Retinoid X receptor (RXR) agonist suppressed the effects of visfatin on EMMPRIN/MMP-9, NF-κB, but not on MAPK activation. In conclusion, we have demonstrated that visfatin enhances atheroma inflammation through the NAMPT-MAPK (p38, ERK1/2)-NF-κB-EMMPRIN/MMP-9 pathway, a key feature of atherosclerotic diseases linked to metabolic disorders.
authors.affiliation: Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 639 Zhizaoju Road, Shanghai, P.R. China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Fan
authors.forename: Shu
authors.initials: S
authors.lastname: Meng
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Jiatian
authors.initials: J
authors.lastname: Cao
authors.forename: Changqian
authors.initials: C
authors.lastname: Wang
mesh_terms: D051926:Basigin / Q000096:biosynthesis*; D002460:Cell Line; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D047495:PPAR gamma; D047488:Retinoid X Receptors; D051926:Basigin; D054409:Nicotinamide Phosphoribosyltransferase; D011972:Receptor, Insulin; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9