title: Tumor necrosis factor-α regulates triggering receptor expressed on myeloid cells-1-dependent matrix metalloproteinases in the carotid plaques of symptomatic patients with carotid stenosis.
abstract: OBJECTIVE
  To determine the relationship between increased triggering receptor expressed on myeloid cells (TREM)-1 and plaque stability in atherosclerotic carotid stenosis.
  
  
  METHODS
  The mRNA transcripts and protein for TREM-1, MMP-1, MMP-9, collagen type I (COL1A1) and collagen type III (COL3A1) were analyzed by qPCR and immunofluorescence in both tissues and VSMCs isolated from atherosclerotic carotid plaques of symptomatic and asymptomatic patients with carotid stenosis.
  
  
  RESULTS
  The TREM-1, MMP-1 and MMP-9 mRNA transcripts were significantly increased (TREM-1, p < 0.01; MMP-1, p < 0.01 and MMP-9, p < 0.001) while COL1A1 and COL3A1 mRNA transcripts were decreased (p < 0.001) in VSMCs isolated from carotid plaques of symptomatic (S) than asymptomatic (AS) patients. Stimulation of cells with TNF-α further increased the mRNA transcripts of TREM-1, MMPs, COL1A1 and COL3A1. Modulation of TREM-1 by treatment with TREM-1 decoy receptor rTREM-1/Fc, and either TREM-1 antibodies or TREM-1 siRNA attenuated the TNF-α-induced expression of MMP-1 and MMP-9 (p < 0.01) and COL1A1 and COL3A1 (p < 0.01) in S compared to AS VSMCs isolated from carotid plaques. Inhibition of NF-kB (BAY 11-7085), JNK (SP600125) and PI3K (LY294002) signaling pathways decreased the expression of TREM-1 (p < 0.01), MMP-1 (p < 0.001) and MMP-9 (p < 0.01) in TNF-α-treated VSMCs isolated from S carotid plaques compared to AS patients.
  
  
  CONCLUSIONS
  Increased expression of TREM-1 in S compared to AS patients involving MMP-1 and MMP-9 suggest a potential role of TREM-1 in plaque destabilization. Selective blockade of TREM-1 may contribute to the development of new therapies and promising targets for stabilizing vulnerable atherosclerotic plaques.
authors.affiliation: Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Velidi H
authors.initials: VH
authors.lastname: Rao
authors.affiliation: Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Rai
authors.affiliation: Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Stoupa
authors.affiliation: Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Saravanan
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE 68178, USA. Electronic address: dkagr@creighton.edu.
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Agrawal
mesh_terms: D000368:Aged; D016893:Carotid Stenosis / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C439971:COL3A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D016207:Cytokines; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D014409:Tumor Necrosis Factor-alpha; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: Atherosclerosis; Extracellular matrix; Inflammation; Matrix metalloproteinases; Transcription factors; Triggering receptor expressed on myeloid cells-1; Tumor necrosis factor-α