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). 17 beta-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 1.0-100nM of E-2 for 24h increased both MMP-9 activity and ANXII expression in a dose-dependent manner (p < 0.05). Preincubation with EGTA (10 mM) 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 mu M significantly reduced macrophage MMP-9 enzymatic activity (p < 0.005) in a dose-dependent manner. In the presence or absence of E-2, simvastatin a] so 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. (c) 2005 Elsevier Ireland Ltd. All rights reserved.