EMMPRIN, also termed CD147 or M6 antigen, is a 58-kDa cell surface glycoprotein described first in tumor cells. It participates in numerous physiological processes, play a central role in tumor metastasis, cell adhesion, angiogenesis, chemoresistance and atherosclerosis [
1],[
2]. EMMPRIN has been reported to stimulates secretion of MMP-9 (matrix metalloproteinase-9) in monocytes [
1],[
3], have strong positive correlation with MMP13 [
4],[
5] or several MMPs in other cells [
6],[
7], and activates MMP-9 in atherosclerotic plaque [
8]. MMP-9 belongs to a family of zinc- and calcium-dependent endopeptidases. It is a 92 kDa protein that regulates numerous cell activities, involving in various physiological functions, such as cell-cell contact, tissue remodeling cell migration and cellular differentiation [
9]. Recent data showed that increased EMMPRIN expression affects plaque stability [
1],[
8], and accelerates the transition from a stable plaque to an unstable plaque in atherogenic cells, such as monocytes/macrophages and coronary smooth muscle cells [
10],[
11]. Despite recent advance in drug treatment and surgical therapies, atherosclerosis remains to be a major cause of death throughout the world. In coronary arteries, plaque disruption is the majority of acute clinical manifestations of atherosclerosis, leading to a subsequent cardiac event, such as AMI and UA. Monocyte-derived macrophages are known to play a critical role in the initiation and progression of atherosclerosis. Over-expression of MMP-9 and EMMPRIN in monocytes/macrophages results in plaque progression and destabilization [
6],[
12]. Plaque rupture is thought to result from the degradation of extracellular matrix components by macrophage-derived matrix metalloproteinases (MMPs) [
13]. Numerous reports have shown that MMP-9 is one of the most important MMPs contributing to plaque rupture, and its expression level is induced in serious coronary atherosclerosis and AMI and UA [
14]. In addition, MMP-9 induces acute plaque disruption in Apoe−/−mice [
15],[
16]. Previous reports demonstrated that MMP-13 is involved in atherogenesis and decreasing plaque stability [
17]. MMP-13 might be overexpressed in both human and experimental atherosclerosis as well [
18],[
19]. All these data indicate that EMMPRIN-mediated MMPs induction is involved in the process of atherosclerotic lesion. Base on these pieces of evidence, we hypothesized that agents suppressing EMMPRIN and MMP-9 expression would be potential therapeutic agents that ameliorate the development of atherosclerosis. All these data indicate that EMMPRIN-mediated MMP induction is involved in the process of atherosclerotic lesion. Based on these pieces of evidence, we hypothesized that agents suppressing EMMPRIN and MMP-9 expression would be potential therapeutic agents that ameliorate the development of atherosclerosis.
During past few years, accumulating evidence has suggested that curcumin has significant inhibitory effect on MMPs in cancer, arthritis and ulcer [
20]. Curcumin (diferuloylmethane), a polyphenol derived from turmeric and curcuma longa, is a pharmacologically safe and effective agent that plays an important role in anti-cancer and anti-inflammatory processes. In atherosclerosis, curcumin suppresses oxLDL (oxidized low-density lipoprotein) induced CD36 expression via inhibiting p38 MAPK phosphorylation [
21], and prevents the decrease of thrombospondin-4 expression in oxLDL treated murine macrophages [
21]. Curcumin inhibits the adhesion of monocytes to endothelial cells [
22], and reduces the migration of HASMCs (human aortic smooth muscle cells) by suppressing MMP-9 expression through down-regulation of NF-κB -dependent pathways [
23]. Furthermore, in vivo data showed that curcumin inhibits atherosclerosis in ApoE(−/−) mice [
22], and blocks the development of atherosclerosis in ApoE/LDLR−/−mice [
24]. Although some studies have suggested the anti-atherosclerosis activity of curcumin, the mechanism by which curcumin regulates MMP-9, MMP-13 and EMMPRIN is currently unknown. The purpose of this study was to uncover the mechanism by which curcumin regulates EMMPRIN, MMP-9 and MMP-13expression during monocyte differentiation.