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  IN THIS Article
 ::  Abstract
 ::  Discussion
 ::  Conclusions
 ::  Acknowledgment
 ::  References

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Year : 2009  |  Volume : 55  |  Issue : 4  |  Page : 284-286

Inhibiting extracellular matrix metalloproteinase inducer maybe beneficial for diminishing the atherosclerotic plaque instability

Department of Cardiology, The Second Affiliated Hospital of Sun Yat-sen University, West Yanjiang Road 107, Guangzhou - 510 120, People's Republic of China, China

Date of Submission02-Feb-2009
Date of Decision31-Jul-2009
Date of Acceptance27-Sep-2009
Date of Web Publication14-Jan-2010

Correspondence Address:
J Wang
Department of Cardiology, The Second Affiliated Hospital of Sun Yat-sen University, West Yanjiang Road 107, Guangzhou - 510 120, People's Republic of China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0022-3859.58936

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 :: Abstract 

Atherosclerotic plaque rupture and local thrombosis activation in the artery cause acute serious incidents such as acute coronary syndrome and stroke. The exact mechanism of plaque rupture remains unclear but excessive degradation of the extracellular matrix scaffold by matrix-degrading metalloproteinases (MMPs) has been implicated as one of the major molecular mechanisms in this process. Convincing evidence is available to prove that extracellular matrix metalloproteinase inducer (EMMPRIN) induces MMP expression and is involved in the inflammatory responses in the artery wall. The inflammation and MMPs have been shown to play a critical role for atherosclerotic lesion development and progression. More recent data showed that increased EMMPRIN expression was associated with vulnerable atherosclerotic lesions. Therefore, we speculate that EMMPRIN may be pivotal for atherosclerotic plaque instability, and hence inhibition of EMMPRIN expression could be a promising approach for the prevention or treatment of atheroma instability.

Keywords: Atherosclerosis, acute coronary syndrome, extracellular matrix metalloproteinase inducer, stroke

How to cite this article:
Xie S, Nie R, Wang J. Inhibiting extracellular matrix metalloproteinase inducer maybe beneficial for diminishing the atherosclerotic plaque instability. J Postgrad Med 2009;55:284-6

How to cite this URL:
Xie S, Nie R, Wang J. Inhibiting extracellular matrix metalloproteinase inducer maybe beneficial for diminishing the atherosclerotic plaque instability. J Postgrad Med [serial online] 2009 [cited 2023 Mar 27];55:284-6. Available from:

Acute coronary syndrome (ACS) and stroke are clinical events that cause considerable immediate morbidity and mortality. The rupture of vulnerable atherosclerotic plaque represents a key process that often leads to ACS or stroke. [1] Over the past several years, it has been recognized that plaque composition such as inflammatory cells and lipid-core plays a more important role than plaque size or stenosis severity in plaque rupture and thrombosis. Convincing evidences have demonstrated that MMPs contribute to the extracellular matrix loss in the fibrous cap and have been implicated in promoting the plaque rupture and the related vascular events. [2],[3],[4],[5],[6] Particular interests have been focused on the role of extracellular matrix metalloproteinase inducer (EMMPRIN) in the plaque development and destabilization. EMMPRIN was first identified on the surface of tumor cells and was found to stimulate adjacent fibroblasts, endothelial cells or tumor cells to produce MMPs, facilitating the invasion of cancer cells. [7] Further studies show that EMMPRIN can also stimulate monocytes and smooth muscle cells to secret these MMPs and plays a vital role in the progress of plaque instability. [8],[9] Moreover, EMMPRIN can initiate the activation of nuclear factor-kB (NF-kB) involved in the inflammatory and proliferative responses of cells linking to atherogenesis and ultimately leading to the synthesis and release of inflammatory cytokines that provide a critical link to adaptive immunity. [1] These inflammatory mediators can exert various atherogenic effects involving the expression of adhesion molecules on endothelial cells, proliferation of smooth-muscle cells, activation of immune cells, and stimulation of the acute-phase response. [10]


The evidence cited above provides us a hypothesis that EMMPRIN is an important factor in the pathology of atherosclerotic plaque instability. Most probably, blocking the expression of EMMPRIN may serve as a novel therapeutic strategy for diminishing atherosclerotic lesion development and atheroma instability.

 :: Discussion Top

Atherosclerosis is a chronic inflammatory disease and immune system plays a key role in atherogenesis. Pro-inflammatory cytokines, such as IL-6 and TNF-a, potently stimulate MMP expression in monocytes and vascular smooth muscle cells; and these pro-inflammatory cytokines control stability of plaques and cause clinical acute vascular events through the regulation of tissue MMPs. [8]

EMMPRIN as a tumor-derived protein has been found to induce MMP production from stromal fibroblasts and is related to tumor invasion. [11] However, recent findings indicate that EMMPRIN plays a pivotal role in the progression of atherosclerosis in many ways, which might include induction of MMP and pro-inflammatory cytokines. [1],[8],[9],[12] EMMPRIN activates NF-kB, which is a critical regulator of innate and adaptive immunity and regulates many key inflammatory genes such as those of IL-6 and TNF-a. As these are linked to atherosclerosis, EMMPRIN's activation of NF- kB constitutes an important step. [1] This might suggest that EMMPRIN-NF-kB pathway is activated in the lesion. Furthermore, evidence shows that Chlamydia pneumoniae induces MMP activity directly in monocytes through an EMMPRIN-dependent pathway in the human atherosclerosis. [12],[13] Some other studies have shown that oxidized low-density lipoproteins can upregulate the EMMPRIN expression of human coronary artery smooth muscle cells, [14] macrophages and foam cells, which suggest a potential mechanism for the synergistic effects of hypercholesterolemia and infection in acceleration of atherosclerosis observed in experimental models [15],[16] and human epidemiological observations; [10],[17] Moreover, recent reports show that the expression of EMMPRIN on monocyte/macrophage differentiation suggests that EMMPRIN may be an important protein in the early phases of directed cell migration and differentiation in atherosclerosis; [1],[8],[9] EMMPRIN may induce a vicious circle in the progress of promoting plaque progression and destabilization by the cellular interactions with monocytes/macrophages, SMCs and platelets stimulating a cascade of MMP activation. [1] In aggregate, these findings indicate that EMMPRIN might be the link among lipid, infection/inflammation, atherosclerosis and plaque rupture.

Schmidt et al., [9] have reported that EMMPRIN expression is upregulated on monocytes in human acute myocardial infraction compared with that in chronic stable angina. After successful therapy, EMMPRIN surface expression on monocytes normalizes. [9] Available evidence also proves that CRP increases EMMPRIN and MMP-9 activity in macrophages resulting in plaque destabilization, and statin can inhibit these effects by inhibiting EMMPRIN expression. [18] Moreover, other experiments have proved that reducing EMMPRIN expression such as by small-interfering RNA, PPAR-a or PPAR-g agonists can hinder monocyte or macrophage secretion of MMPs. [1],[19],[20] Overall, these findings raise the possibility that EMMPRIN could serve as a novel target of therapy in the management of plaque destabilization. It must, however, be conceded that till date no definite in vivo evidence has proved that inhibiting the expression of EMMPRIN in vivo to diminish atherosclerotic lesion development and atheroma instability. This is the new vista for future clinical research.

 :: Conclusions Top

As EMMPRIN plays a critical role not only in immune reactions linking among lipid, infection/inflammation and atherosclerosis, but also in directly inducing MMP secretion and attenuating the fibrous cap of plaques, we hypothesize that EMMPRIN is a key element in the pathology of atherosclerotic plaque instability. The hypothesis provides a new perspective in the study of mechanisms of the EMMPRIN-related progression of atherosclerosis and vascular remodeling. Intervention with the expression of EMMPRIN would be effective in preventing the plaque rupture, and thereby decreasing the incidence of acute coronary syndrome or stroke. However, more experiments in vivo are needed to undertake to prove this hypothesis in the future.

 :: Acknowledgment Top

This study was supported by a grant from National Natural Science Foundation of China to Ruqiong Nie (No. 30770899) and a grant from the Young Teacher Foundation of Sun Yat-sen University to Shuanglun Xie (No. 2008001).

 :: References Top

1.Schmidt R, Bültmann A, Fischel S, Gillitzer A, Cullen P, Walch A, et al. Extracellular matrix metalloproteinase inducer (CD147) is a novel receptor on platelets, activates platelets, and augments nuclear factor kappaB-dependent inflammation in monocytes. Circ Res 2008;102:302-9.  Back to cited text no. 1      
2.Hojo Y, Ikeda U, Takahashi M, Sakata Y, Takizawa T, Okada K, et al. Matrix metalloproteinase-1 expression by interaction between monocytes and vascular endothelial cells. J Mol Cell Cardiol 2000;32:1459-68.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]  
3.Loftus IM, Naylor AR, Goodall S, Crowther M, Jones L, Bell PR, et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption. Stroke 2000;31:40-7.  Back to cited text no. 3      
4.Molloy KJ, Thompson MM, Jones JL, Schwalbe EC, Bell PR, Naylor AR, et al. Unstable carotid plaques exhibit raised matrix metalloproteinase-8 activity. Circulation 2004;110:337-43.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Newby AC. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 2005;85:1-31.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Gough PJ, Gomez IG, Wille PT, Raines EW. Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. J Clin Invest 2006;116:59-69.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]  
7.Biswas C, Zhang Y, DeCastro R, Guo H, Nakamura T, Kataoka H, et al. The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res 1995;55:434-9.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]  
8.Yoon YW, Kwon HM, Hwang KC, Choi EY, Hong BK, Kim D, et al. Upstream regulation of matrix metalloproteinase by EMMPRIN; extracellular matrix metalloproteinase inducer in advanced atherosclerotic plaque. Atherosclerosis 2005;180:37-44.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Schmidt R, Bültmann A, Ungerer M, Joghetaei N, Bülbül O, Thieme S, et al. Extracellular matrix metalloproteinase inducer regulates matrix metalloproteinase activity in cardiovascular cells: Implications in acute myocardial infarction. Circulation 2006;113:834-41.  Back to cited text no. 9      
10.Liu Y, Yu H, Zhang Y, Zhao Y. TLRs are important inflammatory factors in atherosclerosis and may be a therapeutic target. Med Hypotheses 2008;70:314-6.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Suzuki S, Sato M, Senoo H, Ishikawa K. Direct cell-cell interaction enhances pro-MMP-2 production and activation in co-culture of laryngeal cancer cells and fibroblasts: Involvement of EMMPRIN and MT1-MMP. Exp Cell Res 2004;293:259-66.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Choi EY, Kim D, Hong BK, Kwon HM, Song YG, Byun KH, et al. Upregulation of extracellular matrix metalloproteinase inducer (EMMPRIN) and gelatinases in human atherosclerosis infected with Chlamydia pneumoniae: The potential role of Chlamydia pneumoniae infection in the progression of atherosclerosis. Exp Mol Med 2002;34:391-400.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]  
13.Schmidt R, Redecke V, Breitfeld Y, Wantia N, Miethke T, Massberg S, et al. EMMPRIN (CD 147) is a central activator of extracellular matrix degradation by Chlamydia pneumoniae-infected monocytes. Implications for plaque rupture. Thromb Haemost 2006;95:151-8.  Back to cited text no. 13      
14.Haug C, Lenz C, Díaz F, Bachem MG. Oxidized low-density lipoproteins stimulate extracellular matrix metalloproteinase Inducer (EMMPRIN) release by coronary smooth muscle cells. Arterioscler Thromb Vasc Biol 2004;24:1823-9.  Back to cited text no. 14      
15.Blessing E, Nagano S, Campbell LA, Rosenfeld ME, Kuo CC. Effect of Chlamydia trachomatis infection on atherosclerosis in apolipoprotein E-deficient mice. Infect Immun 2000;68:7195-7.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]  
16.Moazed TC, Campbell LA, Rosenfeld ME, Grayston JT, Kuo CC. Chlamydia pneumoniae infection accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. J Infect Dis 1999;180:238-41.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]  
17.Hu H, Pierce GN, Zhong G. The atherogenic effects of chlamydia are dependent on serum cholesterol and specific to Chlamydia pneumoniae. J Clin Invest 1999;103:747-53.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]  
18.Abe N, Osanai T, Fujiwara T, Kameda K, Matsunaga T, Okumura K. C-reactive protein-induced upregulation of extracellular matrix metalloproteinase inducer in macrophages: Inhibitory effect of fluvastatin. Life Sci 2006;78:1021-8.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]  
19.Ge H, Zhang JF, Guo BS, He Q, Wang BY, He B, et al. Resveratrol inhibits macrophage expression of EMMPRIN by activating PPARgamma. Vascul Pharmacol 2007;46:114-21.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]  
20.Zhang J, Ge H, Wang C, Guo TB, He Q, Shao Q, et al. Inhibitory effect of PPAR on the expression of EMMPRIN in macrophages and foam cells. Int J Cardiol 2007;117:373-80.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]  

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