Inflammatory cytokines and oxidized low density lipoproteins increase endothelial cell expression of membrane type 1-matrix metalloproteinase.
We investigated whether inflammatory cytokines or oxidized low density lipoproteins (Ox-LDL) present in human atheroma modulate extracellular matrix degradation by inducing membrane type 1-matrix metalloproteinase (MT1-MMP) expression. Cultured human endothelial cells (EC) constitutively expressed MT1-MMP mRNA and protein with enzymatic activity. Tumor necrosis factor-alpha (TNF-alpha), interleukin-1alpha, or interleukin-1beta caused a time-dependent increase in the steady-state MT1-MMP mRNA levels within 4 h of exposure, peaking about 4-fold by 6 h, and remaining elevated for 12 h. Increased MT1-MMP mRNA correlated with a 2.5-fold increase in MT1-MMP protein in EC membranes. Ox-LDL also increased MT1-MMP mRNA levels that varied with the duration of exposure and degree of LDL oxidation. The increase in MT1-MMP mRNA occurred within 6 h of exposure to Ox-LDL and peaked over 3-fold by 6 h. Ox-LDL, but not native LDL, increased MT1-MMP protein by 2-fold in EC membranes. A combination of TNF-alpha and Ox-LDL was additive in increasing MT1-MMP expression. Nuclear run-on assays showed that TNF-alpha or Ox-LDL augmented steady-state mRNA levels by increased transcription of the MT1-MMP gene. These findings indicate that activation of EC by inflammatory cytokines and/or Ox-LDL increase MT1-MMP expression. Since MT1-MMP promotes matrix degradation by activating pro-MMP-2, these results suggest a novel mechanism whereby cytokines or Ox-LDL may influence extracellular matrix remodeling.
Rajavashisth
T B
TB
Atherosclerosis Research Center, Division of Cardiology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048, USA. rajavashisth@cshs.org
Liao
J K
JK
Galis
Z S
ZS
Tripathi
S
S
Laufs
U
U
Tripathi
J
J
Chai
N N
NN
Xu
X P
XP
Jovinge
S
S
Shah
P K
PK
Libby
P
P
D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D018093:Gelatinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D017931:DNA Primers; D007375:Interleukin-1; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2