Low density lipoprotein from patients with Type 2 diabetes increases expression of monocyte matrix metalloproteinase and ADAM metalloproteinase genes.
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.
Worley
Joanna R
JR
School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, UK. j.worley@uea.ac.uk
Hughes
David A
DA
Dozio
Nicoletta
N
Gavrilovic
Jelena
J
Sampson
Mike J
MJ
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
D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D051722:ADAM Proteins; D020781:Matrix Metalloproteinase 1; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
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