Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells.
Doxycycline is a commonly used broad-spectrum antibiotic. Recently, it has been shown that it also inhibits the activity of mammalian collagenases and gelatinases, an activity unrelated to its antimicrobial efficacy. In this study, we show that doxycycline not only inhibits MMP-8 and MMP-9 (gelatinase B) activity, but also the synthesis of MMPs in human endothelial cells. Doxycycline (50 microM) completely inhibited the phorbol-12-myristate-13-acetate (PMA)-mediated induction of MMP-8 and MMP-9, as measured by Western blotting and gelatin zymography, respectively. The inhibition was also observed at the mRNA level. No effect was observed on the expression of MMP-2 and of the MMP inhibitors TIMP-1 and TIMP-2. Chemically modified tetracyclines (CMTs) showed an inhibition similar to that of doxycycline, albeit less efficient. These observations demonstrate that endothelial cells display a specific regulation of MMPs, which may have implications for the pharmaceutical interaction in angiogenesis and angiogenesis-related diseases.
Hanemaaijer
R
R
Gaubius Laboratory TNO-PG, Leiden, The Netherlands.
Visser
H
H
Koolwijk
P
P
Sorsa
T
T
Salo
T
T
Golub
L M
LM
van Hinsbergh
V W
VW
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004318:Doxycycline / Q000494:pharmacology; D004727:Endothelium / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011480:Protease Inhibitors / Q000494:pharmacology*; D013754:Tetracyclines / Q000737:chemistry / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism