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). 17β-Estradiol (E2) 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 E2 for 24 h 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 E2-mediated MMP-9 activity as did incubation of macrophages with anti-annexin IgG. In the presence or absence of E2 (5 nM), simvastatin treatment in the range of 0.1–5.0 μM significantly reduced macrophage MMP-9 enzymatic activity (p < 0.005) in a dose-dependent manner. In the presence or absence of E2, 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 E2 and that E2-mediated ANXII expression and MMP-9 activity can be prevented by simvastatin. Prevention of E2-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.