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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
S Xie, R Nie, 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, China
| Date of Submission | 02-Feb-2009 |
| Date of Decision | 31-Jul-2009 |
| Date of Acceptance | 27-Sep-2009 |
| Date of Web Publication | 14-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
China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0022-3859.58936
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: https://www.jpgmonline.com/text.asp?2009/55/4/284/58936 |
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]
Hypothesis
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 | |  |
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 | | |
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 | | |
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 | | |
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