Atherosclerosis 180 (2005) 37–44 Upstream regulation of matrix metalloproteinase by EMMPRIN; extracellular matrix metalloproteinase inducer in advanced atherosclerotic plaque Young Won Yoon a , Hyuck Moon Kwon a,∗ , Ki-Chul Hwang c , Eui-Young Choi a , Bum-kee Hong a , Dongsoo Kim a , Hyun-Seung Kim a , Sang Ho Cho c , Kyung Soon Song b , Giuseppe Sangiorgi d a Department of Internal Medicine and Cardiovascular Division, YongDong Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea b Department of Clinical Pathology, YongDong Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea c Division of Cardiovascular research, Yonsei Cardiovascular Center, Seoul, South Korea d Department of Cardiovascular diseases, Instituto Policlinico S Donato, Milan, Italy Received 17 April 2004; received in revised form 19 September 2004; accepted 19 November 2004 Available online 19 January 2005 Abstract From experimental and clinical studies it is known that matrix conservation and degradation by matrix metalloproteinases (MMPs) plays a major role in plaque progression and destabilization with related onset of acute vascular events such as acute coronary syndromes or cere- brovascular accidents. Recently, extracellular MMPs inducer (EMMPRIN) has been reported to induce and activate the expression of MMPs in myocardium and plays an important role in the ventricular remodeling in human heart failure. Similarly to heart failure myocardium, EMM- PRIN may be expressed in human atheroma and play a role in the extracellular matrix (ECM) remodeling and atherogenic cell differentiation. This study was designed to investigate the possible biological role of EMMPRIN in human atheroma. Immunohistochemical analysis for MMPs and EMMPRIN was performed on human carotid endarterectomy specimens and control aortas. EMMPRIN showed significant im- munoreactivity in human atherosclerotic carotid lesions, and was colocalized with macrophage/monocyte infiltrates in atherosclerotic intima, plaque itself and vascular smooth muscle cells (VSMCs). Zymography and Western blot analysis revealed EMMPRIN expression in the carotid atheromas, but not in the control aortas. Human bone marrow monocytes, which were cultured with atherogenic proinflammatory cytokine stimulation revealed increased EMMPRIN and MMPs expressions. ECM remodeling is under the control of induction and inhibition of matrix degrading protease and the novel MMP inducer, EMMPRIN may play a role in influx and differentiation of monocytes and destabilizing atheroma. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Matrix metalloproteinases; EMMPRIN; Destabilizing atheroma 1. Introduction Numerous evidences support the importance of extra- cellular matrix (ECM) in the control of various cellu- lar functions. ECM participates in various processes of atherosclerotic cardiovascular diseases. The balance be- ∗ Corresponding author. Tel.: +82 2 3497 3332; fax: +82 2 573 0112. E-mail address: kwonhm@yumc.yonsei.ac.kr (H.M. Kwon). tween the matrix conservation and its degradation by ma- trix metalloproteinases (MMPs) determine plaque stabil- ity and the related risk of vascular events [1–4]. In par- ticular, macrophage/foam cell-derived matrix metallopro- teinases contribute to the progression of atherosclerosis and have been implicated in promoting the plaque rup- ture. Among the MMP family, previous reports have shown that MMP-2, MMP-9 and MMP-1 are invariably present and play a role in human atherosclerosis [5–8]. However, 0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.11.021