Summary

Protease activity promotes the progression and rupture of atheroscleroticplaques. LDL has been described to become enzymaticallymodified within the vessel wall yielding an atherogenicmoiety (E-LDL).We studied the effect of E-LDL on the activationof plasminogen and matrix metalloproteinases (MMPs) in monocytesand vascular smooth muscle cells (VSMCs) as well as onMMP activation during cellular interactions. Human monocytes,monocytic MonoMac6 cells and human VSMCs were incubatedwith human native LDL (n-LDL) or E-LDL for 24 hours. E-LDLin contrast to n-LDL induced substantial activation of the plasminogenactivation system as well as of the MMP system inmonocytic cells, as measured by enhanced cell surface expressionof the urokinase receptor (uPAR),the extracellular matrixmetalloproteinase Inducer (EMMPRIN) and the membrane type-1 MMPs (MT1-MMP,MMP-14),as well as by secretion of activeuPA, and of MMP-9. Consistently, E-LDL-treated monocytesexhibited increased transmigration through “matrigel”, whichwas specifically abrogated by the MMP inhibitor galardin or theplasmin inhibitor aprotinin. In VSMCs, E-LDL induced MMP-1and MMP-2 secretion. Moreover, monocyte incubation withsupernatants of E-LDL-treated (but not n-LDL-treated) VSMCsstrongly induced MMP-9 in monoytes, which was inhibited byblocking mAb anti-TNF-a .Together, enzymatical modification ofLDL allows a direct activation of MMP expression in monocytesandVSMCs, and indirectly promotes the induction of paracrine,cytokine-mediated intercellular activation processes. Thereby,E-LDL may contribute to atheroprogression, inflammation andplaque rupture.