Cardiovascular Research Advance Access originally published online on March 1, 2008
Cardiovascular Research 2008 79(1):34-41; doi:10.1093/cvr/cvn056
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Cocoa procyanidins inhibit expression and activation of MMP-2 in vascular smooth muscle cells by direct inhibition of MEK and MT1-MMP activities
1 Department of Agricultural Biotechnology and Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921, Republic of Korea
2 Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea
3 Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, Université Louis Pasteur de Strasbourg F-67401, Illkirch, France
* Corresponding author. Tel: +82 2 880 4860; fax: +82 2 873 5095. E-mail address: leehyjo{at}snu.ac.kr(H.J.L)/Tel: +33 3 90 24 41 27; fax: +33 3 90 24 43 13. E-mail address: schini{at}aspirine.u-strasbg.fr(V.B.S.)
Aims: Expression and activation of matrix metalloproteinase (MMP)-2 play pivotal roles in the migration and invasion of human aortic vascular smooth muscle cells (VSMC) originating from normal human tissue, which is strongly linked to atherosclerosis. The present study investigated the possible inhibitory effects of cocoa procyanidin on thrombin-induced expression and activation of MMP-2 in VSMC.
Methods and results: Cocoa procyanidin fraction (CPF) and procyanidin B2, one of major procyanidins in cocoa (3 µg/mL and 5 µM, respectively), strongly inhibited thrombin-induced activation and expression of pro-MMP-2 in VSMC, as determined by zymography. The thrombin-induced invasion and migration of VSMC were inhibited by CPF or procyanidin B2 (P < 0.05), as assessed by a modified Boyden chamber and wound healing assays, respectively. An enzymatic assay data demonstrated that CPF and procyanidin B2 directly inhibited membrane type-1 (MT1)-MMP activity (P < 0.05), and this inhibition of CPF was greater than those of red wine polyphenols. Western blot data showed that CPF and procyanidin B2 inhibited thrombin-induced phosphorylation of extracellular signal-regulated protein kinase but not mitogen-activated protein kinase kinase (MEK) in VSMC. Kinase and pull-down data revealed that CPF and procyanidin B2 inhibited MEK1 activity and directly bound with glutathione-S-transferase-MEK1. In addition, the thrombin-induced invasion and migration and the activation and expression of pro-MMP-2 in VSMC were attenuated by U0126 (a well-known inhibitor of MEK1).
Conclusion: Cocoa procyanidins are potent inhibitors of MEK and MT1-MMP, and subsequently inhibit the expression and activation of pro-MMP-2, and also the invasion and migration of VSMC, which may in part explain the molecular action of antiatherosclerotic effects of cocoa.
KEYWORDS Atherosclerosis; MAP kinase; Matrix metalloproteinase; Smooth muscle
Time for primary review: 28 days
These authors contributed equally to this work.
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