title: Beta-adrenoceptor Activation by Norepinephrine Enhances Lipopolysaccharide-induced Matrix Metalloproteinase-9 Expression Through the ERK/JNK-c-Fos Pathway in Human THP-1 Cells.
abstract: OBJECTIVE
  Atherosclerosis is a chronic inflammatory disease, which leads to thrombosis and acute coronary syndrome. Matrix metalloproteinase-9 (MMP-9) is involved in the stability of the extracellular matrix (ECM) and atherosclerosis plaque. Until now, it is established that lipopolysaccharide (LPS) and norepinephrine (NE) are associated with the pathological process of atherosclerosis. However, the combined effect of LPS and NE on MMP-9 is unclear. We investigated the combined effect of LPS and NE on MMP-9 expression in human monocytes and the mechanism involved in the process.
  
  
  METHODS
  THP-1 cells were cultured and treated with LPS and/or NE. MMP-9 and TIMP-1 gene and protein expression were detected by real time PCR and ELISA, respectively. MMP-9 activity was detected by gelatin zymography. Adrenoceptor antagonists and MAPKs inhibitors were used to clarify the mechanism. Pathway-related proteins were detected by Western blot.
  
  
  RESULTS
  We found that NE enhances LPS-induced MMP-9 and TIMP-1 expression as well as MMP-9 activity in THP-1 cells. This effect is reversed by the beta (β)-adrenoceptor antagonist propranolol, extracellular signal-regulated kinases (ERK) inhibitor U0126, and c-Jun N-terminal kinase (JNK) inhibitor SP600125. NE enhances LPS-induced ERK/JNK phosphorylation. NE up-regulates LPS-induced c-Fos expression, which is counteracted by propranolol, U0126, and SP600125. Furthermore, c-Fos silence reverses the effect of NE on MMP-9 activity.
  
  
  CONCLUSIONS
  Our results suggest that NE enhances LPS-induced MMP-9 expression through β-adrenergic receptor and downstream ERK/JNK-c-Fos pathway. This study may help us to understand the combined effect and mechanism of NE/LPS on MMP-9 expression.
authors.affiliation: Department of Cardiovascular Sciences, First Affiliated Hospital, School of Medicine, Zhejiang University.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yin
authors.forename: Linli
authors.initials: L
authors.lastname: Zhou
authors.forename: Fei
authors.initials: F
authors.lastname: Han
authors.forename: Jie
authors.initials: J
authors.lastname: Han
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zewei
authors.initials: Z
authors.lastname: Sun
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhao
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Liangrong
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000316:Adrenergic alpha-Agonists; D008070:Lipopolysaccharides; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D048049:Extracellular Signal-Regulated MAP Kinases; D048055:Mitogen-Activated Protein Kinase 8; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D009638:Norepinephrine