title: Low density lipoprotein from patients with Type 2 diabetes increases expression of monocyte matrix metalloproteinase and ADAM metalloproteinase genes.
abstract: OBJECTIVE
  Type 2 diabetes is characterised by increased plasma concentrations of pro-inflammatory cytokines [such as tumour necrosis factor - alpha; TNF-alpha] and soluble forms of adhesion molecules involved in leukocyte - endothelial interactions. These molecules are synthesised as transmembrane proteins and the plasma soluble forms are generated by ectodomain cleavage from the cell surface by members of the ADAM [adisintegrin and metalloproteinase] proteinase family. We hypothesised that plasma low density lipoprotein [LDL] from subjects with Type 2 diabetes would influence in vitro monocytic ADAM and matrix metalloproteinase [MMP] gene expression differently compared to control LDL.
  
  
  METHODS
  We examined relative mRNA expression by real time PCR in a monocytic cell line [THP-1] cultured for 4, 8 and 24 hrs with human plasma LDL derived from subjects with [n = 5] or without [n = 4] Type 2 diabetes. Gene expression for MMP-1 and 9, and ADAM - 8, 15, 17 and 28 was studied.
  
  
  RESULTS
  Type 2 diabetes LDL significantly increased gene expression of MMP - 1 [p < 0.01] MMP - 9 [p < 0.001], and ADAM 17 [p < 0.05], - 28 [p < 0.01] and - 15 [p < 0.01] compared to control LDL. Type 2 diabetes LDL had disparate effects on inhibitors of MMP.
  
  
  CONCLUSIONS
  These data suggest that Type 2 diabetes LDL could lead to increased adhesion molecule and TNF alpha cell surface shedding, and vascular plaque instability, by promoting increased expression of ADAM and MMP genes.
authors: School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, UK. j.worley@uea.ac.uk
authors: Joanna R
authors: JR
authors: Worley
authors: David A
authors: DA
authors: Hughes
authors: Nicoletta
authors: N
authors: Dozio
authors: Jelena
authors: J
authors: Gavrilovic
authors: Mike J
authors: MJ
authors: Sampson
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000072198:ADAM17 Protein; D000368:Aged; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008077:Lipoproteins, LDL / Q000302:isolation & purification / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D044465:White People
chemical_list: D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D051722:ADAM Proteins; D020781:Matrix Metalloproteinase 1; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
references: Clin Sci (Lond). 2005 Aug;109(2):189-97
references: 15853770
references: Physiol Rev. 2005 Jan;85(1):1-31
references: 15618476
references: Diabetes Metab Res Rev. 2004 Jul-Aug;20(4):298-304
references: 15250032
references: J Biol Chem. 2003 Dec 19;278(51):51340-6
references: 14534304
references: Metabolism. 2003 Mar;52(3):308-14
references: 12647268
references: Essays Biochem. 2002;38:141-53
references: 12463167
references: Antisense Nucleic Acid Drug Dev. 2001 Apr;11(2):107-16
references: 11334139
references: Am Heart J. 1999 Nov;138(5 Pt 2):S419-20
references: 10539839
references: Endocrine. 2004 Mar-Apr;23(2-3):177-82
references: 15146098