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(Circulation. 2004;110:1861-1867.)
© 2004 American Heart Association, Inc.

Vascular Medicine

Red Wine Polyphenolic Compounds Strongly Inhibit Pro-Matrix Metalloproteinase-2 Expression and Its Activation in Response to Thrombin via Direct Inhibition of Membrane Type 1–Matrix Metalloproteinase in Vascular Smooth Muscle Cells

From the Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, UMR CNRS 7034 (M.-H.O., J.E.B., V.B.S.-K.), and Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM-U 596 (P.A.), Université Louis Pasteur de Strasbourg, France; and Research and Development Center, Yangji Chemicals, An-San, South Korea (M.-H.O.).

Correspondence to Valérie B. Schini-Kerth, PhD, UMR CNRS 7034, Université Louis Pasteur de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, BP 60024, F-67401 Illkirch, France. E-mail schini{at}aspirine.u-strasbg.fr

Received August 5, 2003; de novo received April 15, 2004; revision received June 9, 2004; accepted June 10, 2004.

Background— Regular consumption of moderate amounts of red wine is associated with a reduced risk of coronary disease. Matrix metalloproteinases (MMPs) that participate in extracellular matrix degradation have been involved in atherosclerotic plaque growth and instability. The present study examined whether red wine polyphenolic compounds (RWPCs) inhibit activation of MMP-2, a major gelatinase, in vascular smooth muscle cells (VSMCs).

Methods and Results— Expression of pro-MMP-2 was assessed by Western and Northern blot analyses; MMP-2 activity was assessed by zymography and cell invasion by a modified Boyden’s chamber assay. High levels of pro-MMP-2 and low levels of MMP-2 activity were found in conditioned medium from unstimulated VSMCs. Thrombin induced cell-associated pro-MMP-2 protein expression and MMP-2 activity in conditioned medium of VSMCs. The stimulatory effect of thrombin on MMP-2 activation was prevented by RWPCs in a concentration-dependent and reversible manner. Thrombin markedly increased cell-associated membrane type 1 (MT1)–MMP activity, the physiological activator of pro-MMP-2, and this response was not affected by RWPCs. However, addition of RWPCs directly to MT1-MMP abolished its metalloproteinase activity in a reversible manner. Finally, matrix invasion of VSMCs was stimulated by thrombin, and this response was prevented by RWPCs as efficiently as a broad-spectrum MMP inhibitor.

Conclusions— The present findings demonstrate that RWPCs effectively inhibit thrombin-induced matrix invasion of VSMCs, most likely by preventing the expression and activation of MMP-2 via direct inhibition of MT1-MMP activity. The inhibitory effect of RWPCs on the activation of pro-MMP-2 and matrix degradation might contribute to their beneficial effects on the cardiovascular system.

Key Words: thrombin • metalloproteinases • flavonoid • wine • extracellular matrix

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