基质金属蛋白酶-9与动脉粥样硬化及斑块稳定性

冠心病是严重危害人类健康的常见病和多发病,其病理基础是动脉粥样硬化(AS).AS不稳定斑块的破裂是急性冠状动脉综合征(ACS)包括不稳定型心绞痛、急性心肌梗死、心源性猝死的主要原因.基质金属蛋白酶(MMPs) 是一种Zn2+和Ca2+依赖性的酶家族,能特异性地与细胞外基质(ECM)成分相结合并降解,从而削弱AS斑块纤维帽的结构,促进斑块破裂和血栓形成.     

MMPs在动脉粥样硬化斑块局部的调控机制

基质金属蛋白酶（MMPs）在动脉粥样硬化的发生、发展过程中扮演重要角色,不仅涉及斑块局部炎性细胞浸润、血管平滑肌细胞迁移,还可通过降解细胞外基质促使斑块破裂。动脉粥样硬化斑块局部MMPs的调控机制十分复杂,包括转录、翻译、酶原激活及激活后调节等多个方面。     

MMPs在动脉粥样硬化斑块局部的调控机制

基质金属蛋白酶（MMPs）在动脉粥样硬化的发生、发展过程中扮演重要角色，不仅涉及斑块局部炎性细胞浸润、血管平滑肌细胞迁移，还可通过降解细胞外基质促使斑块破裂。动脉粥样硬化斑块局部MMPs的调控机制十分复杂，包括转录、翻译、酶原激活及激活后调节等多个方面。     

血清基质金属蛋白酶及其组织抑制因子与肝纤维化

在正常肝脏纤维组织中存在着细胞外基质(ECM)的合成与降解的动态平衡。肝纤维化时纤维结缔组织的形成，是由于各种不同致病因子导致ECM合成与降解的失衡所致。基质金属蛋白酶(MMPs)是ECM降解的主要酶系，而其组织抑制因子(TIMPs)通过抑制MMPs，阻止ECM的降解，从而形成或促进肝纤维化。     

基质金属蛋白酶9及其基因多态性与冠心病的相关性研究

基质金属蛋白酶（MMPs）是细胞基质降解所必需的锌离子依赖性的内源性蛋白酶家族,是细胞外基质（ECM）的主要生理性调节物质,在基质成分合成和降解的过程中起着重要的作用。对血管系统的基质成分而言,最重要的MMPs是胶原酶和明胶酶。其中明胶酶-B（即MMP-9）在细胞外基质重塑中具有重要作用,在许多病理损伤方面,如冠状动脉粥样硬化斑块不稳定、心室重塑、心力衰竭进展及心血管疾病预后等中亦扮演着重要的角色。     

基质裂解素基因启动子5A/6A多态与急性心肌梗死的关系

血栓斑块破裂是急性心肌梗死(acute myocardial infarction,AMI)的一个重要的致病因素.尽管血栓斑块破裂的机制目前还不十分明确,已有的研究表明,基质硫蛋白酶(matrix metalloproteinases,MMPs)在人类冠状动脉斑块中广泛存在,能够降解基质[1].其中基质裂解素(stromelysin)可增强MMP活性,降解多种细胞外基质成分[2],在冠状动脉斑块破裂中发挥重要作用.     

肝纤维化与基质金属蛋白酶以及其抑制因子

肝纤维化的形成主要是以胶原为中心的细胞外基质(Extracellular matrix,ECM)在肝脏异常沉积为特点,这种异常的沉积不仅是由于ECM合成增多,更大程度上是因为肝纤维化后期ECM合成和降解的平衡遭到破坏,胶原降解绝对或相对减少而引起的。在ECM降解过程中起主导作用的是基质金属蛋白酶(Matrix metalloproteinases,MMPs)。此外,能够抑制MMPs活性的MMP抑制因子(Tissue inhibitor of metalloproteinases,TIMPs)在ECM代谢调节中也起到重要作用。     

基质金属蛋白酶与冠心病

基质金属蛋白酶(matrix metalloproteinases MMPs)是一组含锌的蛋白质家族，能特异性地降解细胞外基质，可引起斑块基质的降解，促进平滑肌细胞迁移和增殖，在组织重构中起重要作用，已经证实在许多心血管疾病中存在MMPs表达谱的改变。本文就MMPs与冠心病的关系作一综述。     

基质金属蛋白酶与动脉粥样硬化

基质金属蛋白酶 (MMP)降解细胞外基质 (ECM ) ,参与动脉粥样硬化 (AS)的细胞外基质重构过程 ,与AS的形成、斑块破裂及再狭窄密切相关。适度调节金属蛋白酶的活性为防治AS提供了新的靶点。     

基质金属蛋白酶及其抑制物与肝纤维化

肝纤维化(liver fibrosis)是继发于肝脏炎症或损伤后组织修复过程中的代偿反应，由肝脏细胞外基质(ECM)蛋白聚集所致。这种聚集可以是ECM在肝组织内的沉积增加或降解减少的结果。其中，基质金属蛋白酶(MMPs)及其抑制物(TIMPs)在ECM的合成和降解中扮演着重要角色，并为抗纤维化治疗开辟新的途径。     

Atherosclerosis and extracellular matrix

Atherosclerosis is primarily a lesion that progresses due to a series of reactions that are induced by repair of injured intima. The intercellular networking that occurs among smooth muscle cells, macrophages, T lymphocytes and endothelial cells leads to a fibroproliferative response, in which the extracellular matrix (ECM) plays an important role. The ECM, composed of a mixture of vastly different macromolecules including collagen, elastin, glycoproteins and proteoglycans, confers tensile strength and viscoelasticity to the arterial wall. Each component of the ECM possesses unique structural properties that determine its own roles during the development of atherosclerotic plaques. Not only does the ECM provide the structural integrity of the plaques, but it also participates in several key events such as cell migration and proliferation, lipoprotein retention and thrombosis. The various matrix metalloproteinases (MMPs), major enzymes in ECM degradation, and their inhibitors (tissue inhibitors of MMPs) are demonstrated in plaque. An excess of MMPs over inhibitors contributes significantly to ECM destruction rendering the plaque more prone to rupture. Accumulating information on the molecular regulation of ECM synthesis and degradation will help investigators attain a more thorough understanding of the mechanisms of plaque formation and plaque instability and rupture.     

Degraded collagen induces calpain-mediated apoptosis and destruction of the X-chromosome-linked inhibitor of apoptosis (xIAP) in human vascular smooth muscle cells

OBJECTIVE: The extracellular matrix (ECM) of the atherosclerotic lesion is a crucial determinant of its stability, while its degradation by matrix metalloproteinases (MMPs) has been implied in plaque rupture. As accumulation of both MMP-derived collagen fragments and apoptotic smooth muscle cells (SMC) is observed at sites of plaque rupture, we tested the effect of polymerized and degraded type I collagen on the susceptibility of SMC to apoptosis. METHODS: Human SMC were cultured on monomeric or polymerized collagen, and collagen gels were degraded by collagenase. Apoptosis was evaluated using antibodies to active caspases and their substrates. Calpain and caspase activity were measured using fluorogenic substrates. RESULTS: Culture of SMC on polymerized collagen led to increased apoptosis compared to culture on monomeric collagen. In addition, we observed a distinct proteolytic degradation of the endogenous caspase inhibitor X-chromosome-linked inhibitor of apoptosis (xIAP). As MMP-1 was strongly activated in SMC on polymerized collagen, we examined the effect of degraded collagen fragments on xIAP cleavage and apoptosis. Degraded collagen induced rapid proteolytic processing of xIAP identical to that on polymerized collagen. We identified calpains as the proteolytic enzymes responsible for xIAP processing as: i) they were rapidly activated by degraded collagen; ii) recombinant calpain II processed xIAP in an identical manner, and iii) inhibition of calpains by BAPTA or calpeptin abrogated xIAP degradation in intact cells. The functional consequence of xIAP processing by calpains was a loss of its caspase-inhibitory potential. Calpain activation distinctly preceded caspase activation, and inhibition of calpains suppressed apoptosis. CONCLUSIONS: Collagen fragments proteolytically released from the ECM by MMPs may propagate apoptosis of SMC by calpain-mediated inactivation of anti-apoptotic proteins such as xIAP. This may be a novel mechanism of SMC apoptosis in biological settings of enhanced collagen degradation such as vascular remodeling, neointima formation, and atherosclerotic plaque rupture.     

Upstream regulation of matrix metalloproteinase by EMMPRIN; extracellular matrix metalloproteinase inducer in advanced atherosclerotic plaque

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 cerebrovascular 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, EMMPRIN 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 immunoreactivity 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.     

Role of matrix metalloproteinases in vascular remodeling

Vascular remodeling, defined as lasting structural changes in the vessel wall in response to hemodynamic stimuli, plays a role in many (patho)physiological processes requiring cell migration and degradation of extracellular matrix(ECM). Matrix metalloproteinase(MMP) system can degrade most ECM components. Several lines of evidence support a role for MMP system components in the development and progression of atherosclerosis and restenosis after angioplasty. This review article focuses on the role of MMPs in vascular remodeling relevant to atherosclerosis and restenosis after angioplasty.     

Expression of matrix metalloproteinases in cardiac allograft vasculopathy and its attenuation by anti MMP-2 ribozyme gene transfection

OBJECTIVE: Proliferation and migration of vascular smooth muscle cells (SMCs) causes intimal thickening during cardiac allograft vasculopathy (CAV). This process requires the degradation or remodeling of extracellular matrix (ECM) surrounding the cells. Imbalance between degradation and accumulation of ECM also contributes to the development of CAV. In this study, we investigated the contribution of matrix metalloprotenases (MMPs), enzymes regulating ECM turnover, to the development of CAV. METHODS: Donor hearts from male DBA mice were heterotopically transplanted to male B10.D2 recipient mice, and harvested at days 15 and 30 post transplantation. We examined expression MMP-2, -3, -9 and -13 of graft vessels using immunohistochemistry. To clarify the role of MMP-2 in CAV, anti MMP-2 ribozyme was delivered into donor hearts just before transplantation, mediated by a hemagglutinating virus of Japan-liposome complex to specifically suppress MMP-2 activity. RESULTS: All MMPs were immunopositive in SMCs from the slightly thickened neointima at day 15. In the advanced stage of intimal thickening at day 30, in addition to increased number of SMCs, accumulation of collagenous fibers was observed; expression of MMP-3, -9 and -13 was decreased. In contrast, MMP-2 expression remained distinctly positive throughout the progression of the vascular remodeling. After the gene transfer of MMP-2 ribozyme, luminal occlusion was significantly decreased compared to non-treated allografts [25.0+/-6.5 vs. 55.1+/-7.0% (P<0.05)] at day 30 post transplantation. CONCLUSION: MMP-2 is a principle MMP throughout the progression of the vascular remodeling in CAV. Anti MMP-2 therapy could therefore be one of the candidates for a supplemental therapy for CAV.     

What has been learned about the cardiovascular effects of matrix metalloproteinases from mouse models?

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes responsible for extracellular protein degradation in the cardiovascular system. Originally known to play pivotal roles in tissue morphogenesis and wound healing, they have been shown to participate in the complex remodeling processes in blood vessels and the myocardium. The biological activity of MMPs is regulated at different levels: (1) gene expression, (2) activation of precursor proenzyme forms by other MMPs or non-MMP proteins, including thrombin and plasmin, (3) complex formation with surface and extracellular matrix (ECM) components and (4) inhibition by endogenous tissue inhibitors of MMPs, the TIMPs. Murine models with gain or loss of gene function of different MMPs and TIMPS have provided a wealth of experimental data on their critical role in pathological conditions ranging from atherosclerosis, vascular injury, and restenosis to left ventricular function and structural remodeling following chronic pressure and volume overload and ischemia-reperfusion injury.     

Impaired extracellular matrix degradation in aortic vessels of cirrhotic rats

BACKGROUND/AIMS: Thinning of the vascular wall occurs in conductance vessels of cirrhotic rats. Increased nitric oxide synthase (NOS) activity has been involved in the pathogenesis of this phenomenon. Therefore, we assessed the NO-regulated cell signaling pathways participating in vascular remodeling in cirrhosis. METHODS: Aortas were obtained from 15 control and 15 cirrhotic rats. Phosphorylated p38 MAPK and ERK1/2 were used to evaluate the activation of cell MAPK signaling pathways. Extracellular matrix (ECM) turnover was estimated by measuring matrix metalloproteinases (MMPs) activity and protein expression of collagen IV, MMP-2, MMP-9 and tissue inhibitor of MMPs (TIMP)-2. Thereafter, 12 control and 12 cirrhotic rats received Nomega-nitro-L-arginine-methyl-ester or vehicle daily for 11 weeks. RESULTS: Cirrhotic vessels showed a reduction in ERK1/2 phosphorylation, lower MMP activity, decreased MMPs expression and higher collagen IV and TIMP-2 abundance, compared to control rats. Chronic NOS inhibition normalized ERK1/2 phosphorylation and MMPs activity, increased MMPs abundance and decreased TIMP-2 expression in cirrhotic rats. CONCLUSIONS: Vascular remodeling in cirrhotic rats is mediated by down-regulation of cell growth and impaired ERK1/2 activation and subsequent imbalance of ECM turnover. These results further stress the importance of vascular NO overactivity in the reduction of vascular wall thickness in cirrhosis.     

Matrix metalloproteinases: their potential role in the pathogenesis of diabetic nephropathy

Matrix metalloproteinases (MMPs), a family of proteinases including collagenases, gelatinases, stromelysins, matrilysins, and membrane-type MMPs, affect the breakdown and turnover of extracellular matrix (ECM). Moreover, they are major physiologic determinants of ECM degradation and turnover in the glomerulus. Renal hypertrophy and abnormal ECM deposition are hallmarks of diabetic nephropathy (DN), suggesting that altered MMP expression or activation contributes to renal injury in DN. Herein, we review and summarize recent information supporting a role for MMPs in the pathogenesis of DN. Specifically, studies describing dysregulated activity of MMPs and/or their tissue inhibitors in various experimental models of diabetes, including animal models of type 1 or type 2 diabetes, clinical investigations of human type 1 or type 2 diabetes, and kidney cell culture studies are reviewed.     

Metalloproteinases and vulnerable atherosclerotic plaques

Plaque rupture is the main cause of myocardial infarctions and strokes. Ruptured plaques have thin, highly inflamed, and collagen-poor fibrous caps that contain elevated levels of proteases, including metalloproteinases (MMPs), which might weaken plaque caps and promote rupture. On the other hand, MMPs facilitate migration and proliferation vascular smooth muscle cells, which should promote fibrous cap stability. Given the dual effects of MMPs, therapies should selectively target harmful MMPs or the processes that cause MMP activity to rise to destructive levels.     

Tumour invasion and matrix metalloproteinases

Matrix metalloproteinases (MMPs) are proteolytic enzymes which play a major role in tumour invasion. They are mainly produced by host stromal cells in most carcinomas and their expression implies a close co-operation between tumour and stromal cells. Increasing data also demonstrate that, in association with a process of epithelial-to-mesenchymal transition, many MMPs can be expressed by tumour cell themselves. Their most well-known role is the degradation of extra-cellular matrix macromolecules which in turn may regulate tumour invasion in some conditions. This ECM degradation generates some matrikins which are also implicated in tumour invasion and angiogenesis. Moreover, MMPs are also implicated in the degradation of cell adhesion molecules and release and activation of growth factors.