title: Lipopolysaccharide upregulates uPA, MMP-2 and MMP-9 via ERK1/2 signaling in H9c2 cardiomyoblast cells.
abstract: Upregulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and matrix metallopeptidases (MMPs) is associated with the development of myocardial infarction (MI), dilated cardiomyopathy, cardiac fibrosis, and heart failure (HF). Evidences suggest that lipopolysaccharide (LPS) participates in the inflammatory response in the cardiovascular system; however, it is unknown if LPS is sufficient to upregulate expressions and/or activity of uPA, tPA, MMP-2, and MMP-9 in myocardial cells. In this study, we treated H9c2 cardiomyoblasts with LPS to explore whether LPS upregulates uPA, tPA, MMP-2, and MMP-9, and further to identify the precise molecular and cellular mechanisms behind this upregulatory responses. Here, we show that LPS challenge increased the protein levels of uPA, MMP-2 and MMP-9, and induced the activity of MMP-2 and MMP-9 in H9c2 cardiomyoblasts. However, LPS showed no effects on the expression of tissue inhibitor of metalloproteinase-1, -2, -3, and -4 (TIMP-1, -2, -3, and -4). After administration of inhibitors including U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), CsA (calcineurin inhibitor), and QNZ (NFkappaB inhibitor), the LPS-upregulated expression and/or activity of uPA, MMP-2, and MMP-9 in H9c2 cardiomyoblasts are markedly inhibited only by ERK1/2 inhibitors, U0126. Collectively, these results suggest that LPS upregulates the expression and/or activity of uPA, MMP-2, and MMP-9 through ERK1/2 signaling pathway in H9c2 cardiomyoblasts. Our findings further provide a link between the LPS-induced cardiac dysfunction and the ERK1/2 signaling pathway that mediates the upregulation of uPA, MMP-2 and MMP-9.
authors.affiliation: Emergency Department, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Yi-Chang
authors.initials: YC
authors.lastname: Cheng
authors.forename: Li-Mien
authors.initials: LM
authors.lastname: Chen
authors.forename: Mu-Hsin
authors.initials: MH
authors.lastname: Chang
authors.forename: Wei-Kung
authors.initials: WK
authors.lastname: Chen
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.forename: Chang-Hai
authors.initials: CH
authors.lastname: Tsai
authors.forename: Tung-Yuan
authors.initials: TY
authors.lastname: Lai
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9