Role of annexin II in estrogen-induced macrophage matrix metalloproteinase-9 activity: the modulating effect of statins.
Annexin II (ANXII) is a receptor for tissue plasminogen activator and plasminogen for the conversion to plasmin, which, in turn, induces metalloproteinase-9 (MMP-9). 17beta-Estradiol (E(2)) is reported to decrease plasminogen activity inhibitor-1 and increase plasmin and matrix metalloproteinase activity. However, the combined effects of estrogen and statins on macrophage MMP-9 activity and ANXII expression remain unclear. Treatment of J774A.1 macrophages with 1.0-100 nM of E(2) for 24h increased both MMP-9 activity and ANXII expression in a dose-dependent manner (p<0.05). Preincubation with EGTA (10mM) released ANXII from the cell membrane and inhibited the E(2)-mediated MMP-9 activity as did incubation of macrophages with anti-annexin IgG. In the presence or absence of E(2) (5 nM), simvastatin treatment in the range of 0.1-5.0 microM significantly reduced macrophage MMP-9 enzymatic activity (p<0.005) in a dose-dependent manner. In the presence or absence of E(2), simvastatin also decreased ANXII expression (p<0.05). These findings indicate that ANXII plays a central role in modulating the enzymatic activity of MMP-9 in response to E(2) and that E(2)-mediated ANXII expression and MMP-9 activity can be prevented by simvastatin. Prevention of E(2)-mediated activation of MMP-9 by simvastatin suggests that concurrent statin use may account for early event risk of myocardial infarction seen with hormone therapy in recent clinical trials.
Hwang
Juliana
J
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA. Julianah@usc.edu
Hodis
Howard N
HN
Hsiai
Tzung K
TK
Asatryan
Liana
L
Sevanian
Alex
A
D017306:Annexin A2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015153:Blotting, Western; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*
D017306:Annexin A2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D004958:Estradiol; D019821:Simvastatin; D020780:Matrix Metalloproteinase 9