MicroRNA-21 is a unique signature associated with coronary plaque instability in humans by regulating matrix metalloproteinase-9 via reversion-inducing cysteine-rich protein with Kazal motifs

BackgroundCoronary atherosclerotic unstable plaque is one of the leading causes of cardiovascular death. Macrophage-derived matrix metalloproteinase (MMP) 9 is considered for degrading extracellular matrix and collagen, thereby thinning the fibrous cap in plaques. miR-21 is implicated to play an important role in the progression of atherosclerosis. Nevertheless, miR-21 as the biomarker for coronary atherosclerotic unstable plaque remains unknown. We aimed to investigate the prediction role of miR-21 for unstable plaque by pathway study of miR-21 on MMPs and its inhibitor RECK in macrophages.MethodsExpression of miR-21 in macrophages and serum miR-21 as well as MMP-9 was measured in patients with coronary non-calcified plaque, calcified plaque and controls. In vitro experiment was done in human macrophages by over-expressing miR-21 or down-regulating RECK. The regulation of RECK and MMP-9 by miR-21 was evaluated by western blotting and siRNA strategy.ResultsPatients with non-calcified coronary artery lesions had significantly higher miR-21 in macrophages and lower miR-21 serum levels compared to the control and calcified plaque patients. At the same time, the serum levels of MMP-9 were significantly elevated in non-calcified patients. Experiments in vitro indicated that over-expressing miR-21 could induce the expression and secretion of pro-MMP-9 and active-MMP-9 in human macrophages via targeting gene RECK, and knocking down RECK expression by specific siRNA can resemble that of miR-21 over-expression.ConclusionsmiR-21 might be a biomarker for plaque instability by suppressing target gene RECK to promote the expression and secretion of MMP-9 in macrophages.     

Reduction of hippocampal cell death and proteolytic responses in tissue plasminogen activator knockout mice after transient global cerebral ischemia

Knockout mice deficient in tissue plasminogen activator (tPA) are protected against hippocampal excitotoxicity. But it is unknown whether similar neuroprotection occurs after transient global cerebral ischemia, which is known to selectively affect the hippocampus. In this study, we tested the hypothesis that hippocampal cell death in tPA knockout mice would be reduced after transient global cerebral ischemia, and this neuroprotection would occur concomitantly with amelioration of both intra- and extracellular proteolytic cascades. Wild-type and tPA knockout mice were subjected to 20 min of transient bilateral occlusions of the common carotid arteries. Three days later, Nissl and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling staining demonstrated that hippocampal cell death was significantly reduced in tPA knockout brains compared with wild-type brains. Caspase-3 and the two major brain gelatinases (matrix metalloproteinase (MMP)-9 and MMP-2) were assessed as representative measurements of intra- and extracellular proteolysis. Post-ischemic levels of caspase-3, MMP-9 and MMP-2 were similarly reduced in tPA knockouts compared with wild-type hippocampi. Taken together, these data suggest that endogenous tPA contributes to hippocampal injury after cerebral ischemia, and these pathophysiologic pathways may involve links to aberrant activation of caspases and MMPs.     

Association between platelet activation and fibrinolysis in acute stroke patients

We aimed to evaluate platelet activation and fibrinolyis in acute atherosclerotic ischemic stroke patients to clarify the relationship between them. Plasma P-selectin antigen, tissue plasminogen activator (tPA) antigen and activity, and plasminogen activator inhibitor-1 (PAI-1) activity were determined in 60 acute atherosclerotic stroke patients and matched control subjects. All patients were examined within 72 h after stroke onset. The levels of P-selectin, tPA antigen, and PAI-1 activity were all significantly higher in stroke patients compared with controls (all p < 0.0001); the level of tPA activity was significantly lower in patients than that in controls (p < 0.0001). These markers did not change much at different time points within 72 h. In stroke group, P-selectin concentration was highly correlated to PAI-1 activity (r = 0.8433, p < 0.001), but not to tPA antigen (r = -0.1752, p > 0.05), and tPA activity (r = 0.2465, p>0.05), which was further confirmed in the multiple linear regression analysis (F = 47.052, p < 0.0001). Our results indicate increased platelet activation and decreased fibrinolysis in patients with acute atherosclerotic ischemic stroke. Increased platelet activation may be correlated with decreased fibrinolysis.     

人体冠状动脉粥样硬化斑块中氧化低密度脂蛋白和新生血管与斑块稳定性的关系

目的探讨氧化低密度脂蛋白(oxLDL)在人体冠脉稳定斑块和不稳定斑块内的分布、与血管新生之间的关系及其在不稳定斑块形成过程中的可能作用。方法选取经临床和病理解剖检查确诊的急性冠脉综合征(ACS)病例进行免疫组织化学SABC法染色并通过计算机图像分析系统进行量化分析。结果(1)不稳定斑块组内各部位oxLDL的聚集程度均明显高于稳定斑块组。oxLDL主要分布于斑块的肩部,纤维帽及基底部相对较少。oxLDL阳性面积比(‰)分别为肩部:不稳定斑块组20.43±3.12,稳定斑块组17.65±4.22;基底部:不稳定斑块组5.65±1.65,稳定斑块组3.22±1.02;纤维帽:不稳定斑块组4.77±2.03,稳定斑块组2.80±0.22。oxLDL是脂质核心的主要组成部分。(2)斑块肩部Ⅷ因子与oxLDL的阳性面积比呈明显正相关(r=0.8247,P=0.000)。结论不稳定斑块组较稳定斑块组oxLDL的聚集量高,尤其是肩部oxLDL的分布明显高于稳定组,提示斑块内oxLDL含量的多少及分布区域是影响斑块稳定性的重要因素。oxLDL通过促进炎细胞经新生血管在斑块局部聚集而影响斑块的稳定性。     

Coexpression of cyclooxygenase-2 and matrix metalloproteinases in human aortic atherosclerotic lesions

Inflammation appears to have a major role in the development of atherosclerosis. Cyclooxygenase-2 (COX-2) is involved in the inflammatory response via the generation of prostanoids that, in turn, are involved in the production of matrix metalloproteinases (MMPs). This study aimed to investigate atherosclerosis in human aortas for in situ tissue distribution of COX-2, MMPs including MMP-9 and membrane type 1 MMP (MT1-MMP), and tissue inhibitor of metalloproteinase-2 (TIMP-2). Immunohistochemical studies were performed on atherosclerotic lesions of aortas from patients with aortic aneurysms (n = 4) and dissections (n = 3) by using antibodies to COX-2, MMP-9, MT1-MMP, and TIMP-2. Control tissues were obtained from traumatically dissected aortas (n = 2). All specimens from diseased aortas had atherosclerotic lesions ranging from fatty streak to atheromatous plaques. In control, there was no expression of COX-2, MMP-9, and MT1-MMP in all aortic layers. Immunoreactivity for COX-2 was predominantly noted in macrophages and smooth muscle cells (SMCs) of the intima including atherosclerotic plaque itself and the medial layer of the plaque base, as well as in SMCs and endothelial lining of the vasa vasorum in the adventitia. Immunoreactivity for MMP-9 and MT1-MMP was found in the same distribution as that of COX-2. Additionally, the expression of TIMP-2 increased in relation to MMP-9 expression. This study demonstrates that COX-2 is coexpressed with MMP-9 and MT1-MMP, not only by macrophages and SMCs in atherosclerotic lesions, but also in endothelial lining of the vasa vasorum of human aortas. Thus, vascular inflammatory reactions may influence extracellular matrix remodeling by coactivation of MMPs in the development of atherosclerosis and, in turn, the progression of disease.     

Age-related changes in plaque composition: a study in patients suffering from carotid artery stenosis.

OBJECTIVE: The extent of atherosclerotic plaque burden and the incidence of atherosclerosis-related cardiovascular events accelerate with increasing age. The composition of the plaque is associated with plaque thrombosis and acute coronary occlusion. Surprisingly, however, the relation between advancing age and atherosclerotic plaque composition is still unclear. In the present study, we investigated the association between plaque characteristics and advancing age in a population of patients with haemodynamically significant carotid artery stenosis. METHODS: Patients (N=383), ages 39-89 years, underwent carotid endarterectomy (CEA). Morphometric analysis was performed on the dissected atherosclerotic plaques to study the prevalence of fibrous and atheromatous plaques. Picro sirius red, haematoxylin eosin, alfa actin and CD68 stainings were performed to investigate the extent of collagen, calcification, smooth muscle cells and macrophages in carotid plaques, respectively. The presence of metalloproteinases-2 and -9 was assessed by ELISA. RESULTS: With aging, a decrease in fibrous plaques and an increase in atheromatous plaques were observed. This was accompanied by an age-associated decrease in smooth muscle cell content in carotid plaques. Macrophage content slightly increased with age. In addition, total matrix metalloprotease (MMP)-2 was negatively and MMP-9 positively related with age. Differences in plaque phenotype were most prominent for the youngest age quartile compared with older age quartiles. CONCLUSIONS: With increasing age, the morphology of atherosclerotic plaques from patients with carotid artery stenosis changes. Plaques become more atheromatous and contain less smooth muscle cells with increasing age. Local inflammation and MMP-9 levels slightly increased with age in plaques obtained from patients suffering from haemodynamically significant advanced atherosclerotic lesions.     

冠状动脉粥样硬化斑块内血管新生与斑块稳定的关系

目的　比较稳定斑块和不稳定斑块内新生血管形态学分布和数量上的差异 ,探讨新生血管与斑块稳定的关系。方法　从死亡前有急性冠脉综合征发生的 5 2例尸检冠状动脉标本中选取晚期动脉粥样硬化病变的组织块共 92 2块 ,以脂质核心面积是否大于斑块面积的 4 0 %为标准将其分为不稳定斑块组 (15 3块 )和稳定斑块组 (76 9块 ) ,比较两组斑块内新生血管的检出率。由两组随机选取各 4 0个组织块进行第八因子相关抗原抗体的免疫组织化学染色 ,观察阳性物质在斑块内的分布特点并通过计算机图像分析系统进行量化分析。结果　不稳定斑块组新生血管检出率 (80 4 % )显著高于稳定斑块组 (6 6 6 % ,P <0 0 1)。新生血管主要分布在斑块的肩部和基底部 ,纤维帽相对较少 ;不稳定斑块组各部位的新生血管最大密度 [肩部 :(2 2 16± 19 96 )个 /mm2 ,基底部 :(2 1 6 8± 2 0 4 4 )个 /mm2 ,纤维帽 :(3 80± 5 32 )个 /mm2 ]均显著大于稳定斑块组的相应部位 [肩部 :(10 0 4± 11 5 2 )个 /mm2 ;基底部 :(9 6 8± 11 5 2 )个 /mm2 ;纤维帽 :(1 4 8± 2 2 8)个 /mm2 ,P <0 0 5 ]。结论　不稳定斑块组较稳定斑块组新生血管检出率和密度均显著增高 ,提示新生血管与斑块的不稳定性密切相关。除目前较为公认的脂质核心大小     

Atheromatous plaque macrophages produce plasminogen activator inhibitor type-1 and stimulate its production by endothelial cells and vascular smooth muscle cells.

The capacity of macrophages to influence directly and indirectly fibrinolytic processes in atherosclerosis was studied using macrophages isolated from atherosclerotic plaques of patients undergoing surgical repair of distal aortic and femoral arteries. These cells were characterized by their morphology, adherence, esterase positivity, and expression of CD14 antigen. Production of plasminogen activator inhibitor type-1 (PAI-1) by plaque macrophages (6.7 +/- 2.7 ng/10(5) cells/24 hours [mean +/- SEM]) was significantly greater than PAI-1 production by blood monocytes isolated simultaneously from the same patients (1.8 +/- 1.5 ng/10(5) cells/24 hours). Production of tissue type plasminogen activator and urokinase type was not augmented compared to blood monocytes. Conditioned medium from cultured plaque macrophages significantly increased production of PAI-1 by endothelial cells (85 +/- 11% above basal) and vascular smooth muscle cells (25 +/- 10%) in vitro. This response was significantly greater than the response to monocyte-conditioned medium (endothelial cells 38 +/- 11%, vascular smooth muscle cells 2.5 +/- 2.0%). Stimulation of endothelial cell PAI-1 production by macrophage-conditioned medium was partially inhibitable by a monoclonal antibody to transforming growth factor-beta. Tissue type plasminogen activator production by endothelial cells and vascular smooth muscle cells was not affected by plaque macrophage- or monocyte-conditioned medium. Urokinase type plasminogen activator production by endothelial cells and vascular smooth muscle cells was undetectable in control medium and was augmented to similar levels in response to plaque macrophage- and monocyte-conditioned media. These results demonstrate upregulation of PAI-1 production by macrophages in atheromatous plaques and the capacity of soluble products from plaque macrophages to upregulate PAI-1 production by endothelial cells and vascular smooth muscle cells in vitro. These data suggest that macrophages in atherosclerotic plaques may inhibit thrombolysis both directly and indirectly by effects of their soluble products on endothelial cells and vascular smooth muscle cells.     

稳定性,不稳定性心绞痛及急性心肌梗死病人冠状动脉病变的？…

比较稳定型心绞痛、不稳定型心绞痛及急性心肌梗死病人冠状动病变的组织学差异,以阐明其发生的病理学机制。方法选天临床诊明确的ＳＡ、ＵＡ及ＡＭＩ病人死后的尸检收脏标本,对其冠状动脉取材并做组织学及免疫组织化学观察。     

Upregulation of tPA/plasminogen proteolytic system in the periphery of amyloid deposits in the Tg2576 mouse model of Alzheimer's disease

Although the tissue plasminogen activator (tPA)/plasminogen/plasmin proteolytic system is thought to modulate the catabolism of amyloid-β (Aβ), in vivo evidence remains insufficient. In the brain of human amyloid precursor protein transgenic Tg2576 mice, we found co-accumulation of tPA and plasminogen at the periphery of compact amyloid deposits, mainly Aβ42-cored plaques, as well as in the walls of blood vessels with cerebral amyloid angiopathy (CAA). This tPA/plasminogen system contained high levels of proteolytic activity. High levels of tPA were also found in reactive astrocytes with increased Aβ42 expression, whereas plasminogen was found only in neurons. When the brain sections of Tg2576 mice were treated with both tPA and plasminogen, levels of thioflavin-S fluorescence, congophilicity and birefringence in the compact amyloid plaques were significantly reduced, and the ultrastructure of Aβ42-fibrils was disrupted. These results suggest that the assembled Aβ42 may promote upregulation of the tPA/plasminogen proteolytic system, which can modulate the deposition of amyloid plaques in vivo.     

基质金属蛋白酶1与冠状动脉粥样硬化斑块破裂的关系

目的 探讨冠状动脉粥样硬化斑块破裂与基质金属蛋白酶１（ＭＭＰ－１）的关系,以及不稳定斑块中ＭＭＰ－１的来源。方法 收集２０例死于急性心肌梗死、１０例有不稳定心绞痛史,以及１２例有稳定心绞痛史的尸体解剖病例共４２例,从冠状动脉各分支取材,常规病理检查、部分节段行ＭＭＰ－１、平滑肌肌动蛋白、ＣＤ６８、ＣＤ４５ＲＯ和ＣＤ２０洒色。结果 在急性心肌梗死及不稳定心绞痛病例中,均见有斑块破裂伴血栓形成,而在稳     

Increased TIMP/MMP ratio in varicose veins: a possible explanation for extracellular matrix accumulation

Primary varicose veins are functionally characterized by venous back-flow and blood stagnation in the upright position. Dilatation and tortuosity provide evidence for progressive venous wall remodelling, with disturbance of smooth muscle cell/extracellular matrix organization. Affected areas are not uniformly distributed, some areas being hypertrophic, whereas others are atrophic or unaffected. In 12 varicose veins and ten control veins, the proteolytic enzyme/inhibitor balance which may participate in the remodelling of the venous wall was investigated. For this purpose, the presence and enzymatic activity of matrix metalloproteinases (MMP-2, MMP-9), tissue inhibitors of MMPs (TIMP-1, TIMP-2), urokinase-type (uPA) and tissue-type (tPA) plasminogen activators (PAs), and plasminogen activator inhibitor-1 (PAI-1) were quantified by western blot and gelatin or plasminogen-casein zymography. In addition, MMP-2, TIMP-1, TIMP-2, and PAI-1 levels were measured by ELISA. A high TIMP-1 level and a low MMP-2 level/activity were found in varicose veins (p<0.005), resulting in a three-fold increase in the TIMP-1/MMP-2 ratio in varicose versus control veins. Levels of PAs (uPA and tPA) as well as PAI-1 were both lower in varicose veins (p<0.005), with minimal change in the PAI/PA ratio. These results demonstrate that varicose veins are characterized by a higher than normal TIMP/MMP ratio, which may facilitate extracellular matrix accumulation in the diseased venous wall.     

细胞外基质金属蛋白酶诱导因子与尿激酶型纤溶酶原激活物在载脂蛋白E 敲除大鼠动脉粥样硬化斑块表达的意义及相关性*

目的：探究细胞外基质金属蛋白酶诱导因子（ EMMPRIN）与尿激酶型纤溶酶原激活物（ μPA）在载脂蛋 白E 基因（ ApoE）敲除大鼠动脉粥样硬化斑块表达意义及相关性。方法：选择ApoE 敲除大鼠,将其分为对照组 与高脂饮食组,对照组大鼠实施正常饮食喂养,高脂饮食组实施高脂饮食喂养,并分别于喂养的第6、10、14、 18 周处死部分大鼠,采用H-E 染色观测动脉粥样硬化斑块形态, 免疫印迹及RT-PCR 检测主动脉粥样硬化斑块内 EMMPRIN和μPA 的表达及其mRNA表达,并实施组间比较。结果：高脂饮食组大鼠动脉出现明显动脉粥样硬化 斑块,且随着时间的推进,逐渐加重,而对照组大鼠并未出现明显的动脉粥样硬化斑块;喂养第6、10、14、18 周时高脂饮食组大鼠主动脉内EMMPRIN和μPA 的表达及其mRNA表达均明显高于对照组;EMMPRIN与μPA 表 达呈正相关。结论： EMMPRIN与μPA 在动脉粥样斑块中的表达水平呈正相关关系,两者可能参与动脉粥样硬化 斑块的形成并发挥促进作用。     

Hepatic fibrosis: role of matrix metalloproteases and TGFbeta

Liver fibrosis and cirrhosis involve multiple cellular and molecular events that lead to deposition of an excess of extracellular matrix proteins and increase the distortion of normal liver architecture. Etiologies include chronic viral hepatitis, alcohol abuse and drug toxicity. Degradation of these matrix proteins occurs predominantly as a result of a family of enzymes called metalloproteases (MMPs) that specifically degrade collagenous and non-collagenous substrates. Matrix degradation in the liver is due to the action of at least four of these enzymes: MMP-1, MMP-2, MMP-3 and MMP-9. In the fibrinolytic system, MMPs can be activated through proteolytic cleavage by the action of urokinase plasminogen activator; a second mechanism includes the same metalloproteases. This activity is regulated at many levels in the fibrinolytic system. The main regulator is the PAI-1. This molecule blocks the conversion of plasminogen into plasmin, and the MMP cannot be activated. At a second level, the inhibition is possible by binding to inhibitors called TIMP that can inhibit the proteolitic activity even when the MMPs had been previously activated by plasmin. During abnormal conditions, overexpression of these inhibitors is directed by the transforming growth factor-beta that in a fibrotic disease acts as an extremely important adverse factor.     

T-cell subpopulations and macrophages in stable and unstable coronary atherosclerotic plaques

Unstable atherosclerotic plaques are a cause of acute myocardium infarction. Because peripheral blood mononuclear cells are often present in atherosclerotic plaques, we've examined T-cells (CD4, CD8) and macrophages (CD68) in the different areas of atherosclerotic plaques. The cells were counted individually in the center, shoulder at the bottom and in the cap of plaque. All types of studied cells prevailed in the unstable plaque cap than in the stable one (p < 0.05). CD4 and CD68 cells dominated in the shoulder of atherosclerotic plaque (p < 0.05). The difference between the numbers of macrophages at the bottom or in the center of stable and unstable plaques was statistically insignificant (p > 0.05). Prevalence of peripheral blood mononuclears in the cap and at the periphery of unstable plaques points their participation in the development of atherosclerotic plaque instability.     

Metalloproteinases in development and progression of vascular disease

Remodeling of the vascular wall plays a role in many physiological processes, but also in the pathogenesis of major cardiovascular diseases such as restenosis and atherosclerosis. Remodeling requires proteolytic activity to degrade components of the extracellular matrix; this can be generated by the matrix metalloproteinase(MMP) system alone or in concert with the fibrinolytic (plasminogen/plasmin) system. Several lines of evidence suggest that the MMP system plays a role in vascular smooth muscle cell migration and neointima formation after vascular injury. In atherosclerotic lesions, active MMPs may contribute to plaque destabilisation by degrading extracellular matrix components, but may also promote aneurysm formation by proteolytic degradation of the elastic lamina.The MMP system may therefore represent a potential therapeutic target for treatment of restenosis or atherosclerosis.     

Chlamydia pneumoniae enhances cytokine-stimulated human monocyte matrix metalloproteinases through a prostaglandin E2-dependent mechanism

Exposure of human monocytes to Chlamydia pneumoniae resulted in a significant enhancement of matrix metalloproteinase (MMP) 1 and 9 production following stimulation with tumor necrosis factor alpha and granulocyte monocyte-colony stimulating factor. The effect of C. pneumoniae on monocyte MMPs was mediated through the induction of prostaglandin E(2). These findings may have implications for atherosclerotic plaque rupture.     

Pregnancy-associated plasma protein A as a marker of acute coronary syndromes

BACKGROUND: Circulating markers indicating the instability of atherosclerotic plaques could have diagnostic value in unstable angina or acute myocardial infarction. We evaluated pregnancy-associated plasma protein A (PAPP-A), a potentially proatherosclerotic metalloproteinase, as a marker of acute coronary syndromes. METHODS: We examined the level of expression of PAPP-A in eight culprit unstable coronary plaques and four stable plaques from eight patients who had died suddenly of cardiac causes. We also measured circulating levels of PAPP-A, C-reactive protein, and insulin-like growth factor I (IGF-I) in 17 patients with acute myocardial infarction, 20 with unstable angina, 19 with stable angina, and 13 controls without atherosclerosis. RESULTS: PAPP-A was abundantly expressed in plaque cells and extracellular matrix of ruptured and eroded unstable plaques, but not in stable plaques. Circulating PAPP-A levels were significantly higher in patients with unstable angina or acute myocardial infarction than in patients with stable angina and controls (P<0.001). A PAPP-A threshold value of 10 mlU per liter identified patients who had acute coronary syndromes with a sensitivity of 89.2 percent and a specificity of 81.3 percent. PAPP-A levels correlated with levels of C-reactive protein and free IGF-I, but not with markers of myocardial injury (troponin I and the MB isoform of creatine kinase). CONCLUSIONS: PAPP-A is present in unstable plaques, and circulating levels are elevated in acute coronary syndromes; these increased levels may reflect the instability of atherosclerotic plaques. PAPP-A is a new candidate marker of unstable angina and acute myocardial infarction.     

Evaluation of stromal metalloproteinases and vascular endothelial growth factors in a spontaneous metastasis model

This study aims to investigate MMP2 and MT1-MMP protein as well as VEGF-C and VEGF-D mRNA expression in tumor cells and distant organs considered to be targets for metastasis in a tumor spontaneous metastasis model previously described. Cultured tumor cells, able to express pro-MMP2, MMP2, pro-MMP9, and MT1-MMP, develop tumor growth and metastasis, mainly in the liver and spleen, when they are injected in the mammary pad gland of Wistar rats. Immunohistochemical studies of tumor masses showed small groups of tumor cells staining for MT1-MMP but not for MMP2. In the liver, tumor metastatic foci and a stromal positive staining for both MMP2 and MT1-MMP were shown. The spleen and lymph nodes, with only scattered metastatic cells, did not show MMPs immunostaining. Using RT-PCR, a significantly higher VEGF-C and VEGF-D gene expression was shown in the liver of tumor-bearing rats respect to normal rats, whereas spleen and lymph nodes did not show significant differences in mRNA VEGF-C/D levels. Taken together, our results suggest that the stroma microenvironment of target organs for metastasis has the ability to produce MMPs and VEGFs that facilitate the anchorage of tumor cells and promote tumor cell growth and angiogenesis.     

Supplementary taurine may stabilize atheromatous plaque by antagonizing the activation of metalloproteinases by hypochlorous acid

The rupture of atherosclerotic plaque, responsible for triggering the majority of myocardial infarctions, presumably requires proteolysis of collagen fibers and other protein components of the intercellular matrix. This is achieved by activated matrix metalloproteases (MMPs) secreted by intimal macrophages and foam cells. MMPs are synthesized as inactive pro-enzymes in which coordinate binding of the thiol group of a key cysteine residue to the active-site zinc atom blocks proteolytic activity. Physiological activation of MMPs is mediated, in large measure, by phagocyte-derived hypochlorous acid (HOCL), which can oxidize the zinc-bound thiol to sulfinic acid, thus freeing the active-site zinc. HOCL also encourages proteolysis of ground substance by inactivating proteins such as TIMP-1 that are physiological inhibitors of MMPs. In vivo, the unrestrained oxidant activity of HOCL is opposed by taurine, which reacts spontaneously with HOCL to generate taurine chloramine, much more stable than HOCL. Taurine chloramine has less impact than HOCL on MMP activation, and does not impair the activity of TIMP-1. Since tissue levels of taurine can be boosted via supplementation, taurine may thus have potential for stabilizing plaque and thereby warding off infarction--an effect that should be reinforced by taurine's platelet-stabilizing activity. In light of recent epidemiological evidence that increased expression of myeloperoxidase - the enzyme which generates HOCL--is an important risk factor for coronary disease, supplemental taurine may indeed have broader utility for suppressing both the genesis and the rupture of atherosclerotic plaque.