Abstract 19488: Serpin-8 Prevents Migration of Macrophages by Inhibiting a Proprotein Convertase-Driven Activation of MT1-MMP
Introduction: Accumulation of macrophages and their expression of matrix metalloproteinases (MMPs) play a pivotal role for the induction and progression of atherosclerotic plaque instability. Recently we demonstrated that the proprotein convertase furin initiates a macrophage MT1-MMP-mediated proteolytic cascade of pro-MMP-2 activation derived from vascular smooth muscle cells. It was shown that the human proteinase inhibitor 8 (serpin-8), a widely expressed 45-kDa ovalbumin-type serpin, exhibits inhibitory activity towards furin. Therefore the aim of the present study was to investigate the role of serpin-8 for furin-driven MT1-MMP activation and macrophage migration.
Methods and results: Macrophage differentiation of human circulating monocytes as well as of human monocytic THP-1 cells (50nM PMA, 48 hrs) was accompanied by increased expression and activity of furin and MT1-MMP protein levels. Accordingly we found an increased expression of mRNA levels of furin and MT1-MMP during macrophage maturation (p<0.05, n=3 for all further parameters). In contrast serpin-8 protein was lost during macrophage differentiation. Re-expression of serpin-8 in macrophages inhibited furin activity and subsequent pro-MT1-MMP activation, comparable to the specific pharmacological furin-inhibitor decanoyl-RVKR chloromethylketone (dec-CMK, 50μmol/l). Likewise, inhibition of furin, either with serpin-8 or dec-CMK prevented MT1-MMP dependent activation of exogenously added pro-MMP-2 and inhibited macrophage matrigel invasion, comparable to the effects of direct MMP-inhibition with the MMP-inhibitiors GM6001, TIMP-2 or TIMP−3.
Conclusion: The present study demonstrates that monocyte/macrophage differentiation is characterized by increases in furin activity and decreased expression of its inhibitor serpin−8. This facilitates macrophage MMP-activation and invasion. Targeted activation of the proteinase inhibitor serpin-8 might represent a novel therapeutic strategy for the treatment of atherosclerotic plaque instability.
- © 2010 by American Heart Association, Inc.