基质金属蛋白酶-2与冠状动脉粥样硬化性疾病的研究进展

基质金属蛋白酶-2是基质金属蛋白家族中的一个重要成员,在生理情况下参与人体的正常发育,病理状态下潜在基质金属蛋白酶-2被激活,通过削减斑块纤维帽参与心室重构在多种心血管疾病的发生、发展中起重要作,并且有望成为反映心血管疾病的一种生物标志物,而对基质金属蛋白酶-2的调节将是一个可能的治疗靶点。现就基质金属蛋白酶-2的基因、蛋白、活性调节、信号转导及其在冠状动脉粥样硬化性心脏病中的研究进展予以综述。     

氧化低密度脂蛋白增加巨噬细胞基质金属蛋白酶-9和-12的表达

为探讨巨噬细胞在动脉粥样斑块不稳定性中的作用机制，观察致动脉粥样硬化的主要炎性因子—氧化低密度脂蛋白(oxLDL)，对巨噬细胞基质金属蛋白酶MMP—9和MMP—12表达和分泌的影响。在体外分离培养小鼠腹腔巨噬细胞，以不同浓度低密度脂蛋白(LDL)、氧化低密度脂蛋白(oxLDL)作用细胞；作用6h后用RT—PCR检测MMP—9，MMP—12mRNA表达，作用24h后用Western blot和β—酪蛋白酶谱法检测MMP—9，MMP—12酶蛋白的分泌及活性。ox—LDL增强巨噬细胞MMP—9，MMP—12mRNA表达和酶蛋白的分泌及活性，对MMP—12的诱导作用更为显著且呈浓度依赖性。表明oxLDL可能通过同时上调巨噬细胞基质金属蛋白酶MMP—9和MMP—12表达和分泌而提高富含巨噬细胞粥样斑块的不稳定性。     

急性冠状动脉综合征患者血浆基质金属蛋白酶及其抑制因子的变化

目的：研究急性冠状动脉综合征患者血浆基质金属蛋白酶（MMP-9）及其抑制因子（TIMP-1）的变化。方法：采用夹心酶免疫定量分析技术，测定30例急性冠状动脉综合征患者、29例稳定型心绞痛患者和17例正常对照血浆MMP-9和TIMP-1的变化。结果：3组间年龄、性别、总胆固醇、甘油三脂、高密度脂蛋白胆固醇和低密度脂蛋白胆固醇无显著差异。急性冠脉综合征组高敏C反应蛋白(4.336±1.334) mg/L、MMP-9 (13.145±9.796) μg/L、TIMP-1 (1.363±0.605) μg/L、MMP-9/TIMP-1 (10.013±7.195) 显著高于稳定型心绞痛组[ 分别为(2.205±0.458) mg/L、(2.206±1.996) μg/L、(0.688±0.389) μg/L和(3.249±1.987) ]和正常对照组[ 分别为(1.625±0.434) mg/L、(1.663±1.271) μg/L、(0.583±0.421) μg/L和(5.169±7.416) ]，MMP-9与hs-CRP、TIMP-1、MMP-9/TIMP-1呈正相关。结论：急性冠脉综合征患者存在着由炎症反应导致的以MMP-9升高为主的MMP-9/TIMP-1失衡状态，血浆MMP-9/TIMP-1有可能作为反映急性冠脉综合征患者脆性斑块的指标。     

基质金属蛋白酶与动脉硬化斑块稳定性的关系

动脉硬化是一个逐渐发生、发展的病理过程，通常在症状出现前20-30年就已经出现动脉硬化病变。因此，在临床症状出现前已经历了一个无症状的寂静期。随着动脉造影技术、血管内超声技术的应用、尸解及动物实验的大量研究也证实，依据斑块的解剖学特点将斑块分为稳定及不稳定的两种类型更为合理．即稳定性及不稳定性斑块也是动脉粥样硬化斑块存在的两种状态。大量研究认为，动脉粥样硬化是病灶的结构和组成而非血管狭窄程度发生高危事件的决定因素。但是，目前尚无有效识别不稳定性斑块及预防不稳定斑块破裂的措施。因此，研究血清标记物及相应的干预措施，具有重要的临床研究意义。     

大肠癌组织中基质金属蛋白酶-2和基质金属蛋白酶-9的表达

目的：探讨大肠癌组织中基质金属蛋白酶－2（MMP－2）和基质金属蛋白酶－9（MMP－9）的表达与临床病理参数之间的关系。方法：应用免疫组织化学S－P法检测87例大肠癌组织中MMP－2和MMP－9的表达情况。结果：87例大肠癌组织中MMP－2和MMP－9的表达阳性率分别为56．3％和55．2％。MMP－2和MMP－9在侵及肌层的阳性表达率明显低于侵及浆膜层，淋巴结转移阳性组高于淋巴结转移阴性组，差异均有显著性（P＜0．05）。Dukes分期中，C、D期中MMP－2和MMP－9的阳性表达率明显高于A、B期（P＜0．05），而与性别、年龄、肿瘤部位、组织学类型和分化程度均无关（P＞0．05）。结论：MMP－2和MMP－9可能在大肠癌浸润转移过程中发挥重要作用。     

基质金属蛋白酶与胎膜早破

胎膜早破（preterm premature of the fetal membranes，PROM）和足月前胎膜早破（P—PROM）是威胁母婴健康的常见并发症。PROM的发生率是10％；P—PROM的发生率是2％-3.5％，30％-40％的早产与此有关，而85％的新生儿发病率和死亡率由早产引起。胎膜破裂后，由于屏障作用消失，将可能引起羊膜腔感染、围产期感染、败血症、新生儿窒息等严重的并发症，如果处理不当可危及母儿安全与健康，因此PROM一直受到产科界的关注。     

血清基质金属蛋白酶与糖尿病血管病变的关系

目的血清基质金属蛋白酶 (MMPS)具有促进炎细胞浸润、平滑肌细胞增殖和新生血管形成作用。本文探讨其与2型糖尿病血管病变的关系。方法检测50例2型糖尿病 ,合并大血管病变34例 ,微血管病变10例 ,对照组20例。用ELISA法测定MMPS值。结果2型糖尿病MMPS -1值为(161.3±12.3)pg/ml,伴大血管组为(178.4±14.6)pg/ml,伴微血管病变组为(160.6±10.1)pg/ml。对照组(119.4±10.2)pg/ml。基质金属蛋白酶在空腹血糖受损和IGT时即开始表达升高 ,在伴大血管病变时MMPS -1表达升高显著 ,与对照组比较 (P<0.01) ,本组大血管病变组与微血管病变组比较 (P<0.05) ,提示2型糖尿病患者均有不同程度的基质金属蛋白酶表达升高。结论基质金属蛋白酶升高程度可反映2型糖尿病患者血管病变程度 ,是较可靠的指标     

基质金属蛋白酶及其抑制剂与疾病的关系

基质金属蛋白酶（ＭＭＰ）和金属蛋白酶组织抑制剂（ＴＩＭＰ）是细胞外基质（ＥＣＭ）合成及降解代谢平衡调节中两个重要的酶系。ＭＭＰ分为三类，可水解各类胶原及基质糖蛋白、蛋白多糖等成分。ＴＩＭＰ也有三种，均能与ＭＭＰ成员结合成复合物而抑制其活性。两大酶系的调节异常可导致ＥＣＭ的代谢失衡，在器官硬化、肾脏疾病及肿瘤浸润等多种病理过程中起到十分重要的作用。     

基质金属蛋白酶在多发性硬化发病中的作用机制及治疗现状

多发性硬化（MS）是中枢神经系统炎性脱髓鞘疾病,基质金属蛋白酶是一组蛋白水解酶,有重要的病理和生理作用,近年的研究表明它在（MS）的发生和疾病进展中都具有重要作用,参与主要的发病过程,具有多种发病机制,抑制其活性具有有效的治疗意义。     

血管内皮细胞产生基质金属蛋白酶的作用与机制

基质金属蛋白酶 (MMP)是一类以锌为辅助因子的蛋白酶家族 ,在体内主要降解细胞外基质 ,参与炎症反应、肿瘤扩散转移和缺血缺氧损伤等。内皮细胞在一些细胞因子和体内活性物质刺激下产生MMP。MMP产生的调节主要发生在转录水平 ,在体内其活性受到特异性抑制剂TIMP的调节     

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     

膝关节软骨中基质金属蛋白酶13及其组织抑制剂1的表达

背景：基质金属蛋白酶组织抑制剂1是与基质金属蛋白酶13相对应的拮抗剂,两者间表达水平和功能活性的平衡对细胞外基质的代谢状态起着重要作用,但在DH豚鼠骨关节炎发生发展过程中,两者表达水平,尤其两者表达水平比值的变化尚不明确。 目的：探讨不同月龄DH豚鼠关节软骨中基质金属蛋白酶13、基质金属蛋白酶组织抑制剂1表达比值的变化及其与DH豚鼠增龄性原发骨性关节炎发病过程中软骨退变程度的关系。 方法：选取2,4,8,12月龄雌性DH各6只,取膝关节观察关节软骨的大体形态后常规脱钙、包埋、制作石蜡切片,用于VG染色行组织学观察,采用Mankin评分系统定量分析关节软骨退变情况,采用免疫组织化学方法检测膝关节软骨中基质金属蛋白酶13、基质金属蛋白酶组织抑制剂1表达情况,应用 Image pro-Plus 6.0软件对免疫组织化学阳性蛋白表达情况进行积分吸光度计算。线性回归分析判断Mankin评分与基质金属蛋白酶13/基质金属蛋白酶组织抑制剂1比值的相关性。 结果与结论：DH豚鼠2月龄膝关节软骨无关节炎表现,4 月龄出现轻度软骨退变,并随月龄增加进行性加重,Mankin评分随月龄增加逐渐增高,各组之间的差异均有显著性意义(P < 0.05)。基质金属蛋白酶13、基质金属蛋白酶组织抑制剂1的表达均随月龄进行性增加,两者比值与Mankin评分呈正相关性(P < 0.05)。结果提示DH豚鼠4月龄出现膝关节软骨退行性变化,随月龄增加而进行性加重,其病理改变与基质金属蛋白酶13/基质金属蛋白酶组织抑制剂1表达失衡有关。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

白细胞介素1β对软骨细胞miR-27b和基质金属蛋白酶13蛋白表达的影响

BACKGROUND: Matrix metalloproteinase-13 is most active in the degradation of collagen type II in the extracellular matrix of cartilage. Interleukin-1 (IL-1) is thought to be the inducer of matrix metalloproteinases, and participates in the degradation and degeneration of articular cartilage. OBJECTIVE: To study the influence of IL-1β on microRNA-27b (miR-27b) and matrix metalloproteinase-13 expression of chondrocytes in rats. METHODS: Chondrocytes isolated from seven male Wistar rats were cultured and divided into IL-1β stimulation group and control group. No stimulus was given in the control group; 10 μg/L of serum free medium was used to culture rat chondrocytes in the IL-1β stimulation group. Cell growth was observed at 0, 24, and 48 hours under an inverted microscope. miR-27b and matrix metalloproteinase-13 expression in the cultured chondrocytes were detected. RESULTS AND CONCLUSION:The relative expression of matrix metalloproteinase-13 in rat chondrocytes was gradually increased when induced by IL-1β at 0, 24, and 48 hours (P < 0.05). Expression of miR-27b and miR-31 in rat chondrocytes at 24 and 48 hours induced by IL-1β gradually decreased (P < 0.05); conversely, expression of MiR-26a, miR-26b, miR-23, and miR-204 gradually increased (P < 0.05). After 48 hours of IL-1β induction, expression of miR-27b was the lowest in rat chondrocytes (P < 0.05). These findings suggest that IL-1β inhibits miR-27b expression, strengthens the expression of matrix metalloproteinase-13, and damages chondrocytes, contributing to both the onset and progression of osteoarthritis. 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Correlation between coronary plaque burden and heart weight

It is unclear if the extent of coronary atherosclerosis is associated with increase in heart muscle mass. We retrospectively reviewed autopsy reports of sudden coronary deaths occurring in a statewide medical examiner system over a one-year period. Cardiomegaly was assessed by height, and given a score of 0–4 based on amount above the upper limit of normal range. Coronary disease was quantitated as number of epicardial arteries with ≥75% cross sectional luminal narrowing. There were 100 hearts with one-vessel disease, 77 with two-vessel disease, and 59 with three- or four-vessel diseases. The extent of disease was less in women than men (P = 0.002). Healed infarcts were present in 21% of women and 36% of men. Cardiomegaly was present in 50% of women and 69% of men. By univariate analysis, in patients without hypertension, cardiomegaly score in the three- or four-vessel disease group was significantly greater than in the one-vessel disease group (P = 0.005), as well as the frequency of cardiomegaly (P = 0.001). Hearts with myocardial scar had a more frequent cardiomegaly (P = 0.0004) and higher cardiomegaly score (P = 0.004) than without myocardial scar. Moreover, by multivariate analysis, body mass index (P < 0.0001), extent of coronary disease (P = 0.02) and healed infarct (P = 0.04) were positively associated with cardiomegaly. We conclude that there is a significant correlation between the extent of coronary atherosclerosis and cardiac hypertrophy independent of age and body mass index in sudden coronary deaths as well as healed infarct. These data support a causative association between chronic ischemia and cardiomegaly     

Matrix metalloproteinase-1 treatment of muscle fibrosis

The onset of scarring after injury may impede the regeneration and functional recovery of skeletal muscle. Matrix metalloproteinase-1 (MMP-1) hydrolyzes type I collagen and thus may improve muscle regeneration by resolving fibrotic tissue. We examined the effect of recombinant human MMP-1 on fibrosis in the lacerated gastrocnemius muscle of NOD/scid mice, allowing treatment potential to be ascertained in isolation from immune response. The efficacy of proMMP-1 and active MMP-1 were compared with or without poly(ethylene glycol) (PEG) modification, which was intended to increase the enzyme's stability. Active MMP-1 was most effective in reducing fibrosis, although treatment with proMMP-1 was also beneficial relative to controls. PEG-modified MMP-1 had minimal activity in vivo, despite retaining activity towards a thioester substrate. Moreover, the modified enzyme was inactivated by trypsin and subtilisin at rates comparable to that of native MMP-1. These results and those of computational structural studies suggest that modification occurs at the C-terminal hemopexin domain of MMP-1, which plays a critical role in collagen turnover. Site-specific modifications that spares catalytic and substrate binding sites while protecting susceptible proteolytic digestion sites may be beneficial. We conclude that active MMP-1 can effectively reduce muscle scarring and that its activity is related to the ability of the enzyme to digest collagen, thereby facilitating remodeling of the injured muscle.     

椎间盘退变患者血清及髓核组织中基质金属蛋白酶1及抑制剂1的表达

BACKGROUND:Matrix metalloproteinases are now generally considered to be able to degrade all extracellular matrices. Hypersecretion of matrix metalloproteinases or reduction in tissue inhibitors of matrix metalloproteinases leads to destruction of the dynamic balance of extracellular matrix. OBJECTIVE: To elucidate the role of matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1 in the pathogenesis and progression of intervertebral disc degeneration. METHODS: A total of 60 patients with intervertebral disc degeneration were included. Mild, moderate, and severe degeneration signals appeared on MRI imaging of the patients. Meanwhile, 20 patients with vertebral fracture, mainly cervical spine fracture, were selected as the control group. Venous blood samples were collected before the surgery; the intervertebral disc specimens were sequentially collected. RESULTS AND CONCLUSION: Serum and tissue levels of matrix metalloproteinase-1 in patients with intervertebral disc degeneration were significantly increased compared with the control group (P < 0.05), and furthermore those were significantly increased in patients with severe disc degeneration compared with patients with mild and moderate disc degeneration (P < 0.05). However, serum and tissue levels of tissue inhibitors of matrix metalloproteinases did not differ significantly between the disc degeneration and control groups (P > 0.05). These results indicate that hypersecretion of matrix metalloproteinase-1 occurs in patients with intervertebral disc degeneration; however, the expression of tissue inhibitor of matrix metalloproteinase-1 is not correlated with intervertebral disc degeneration. 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

氧化型胆固醇下调血管平滑肌细胞金属蛋白酶组织抑制剂基因表达

目的:研究氧化型胆固醇对血管平滑肌细胞MMP-9及TIMP-1表达的影响。方法:离体培养兔主动脉血管平滑肌细胞,分别用胆固醇、Triol与25-OH负载细胞,狭缝杂交测定TIMP-1mRNA表达,细胞免疫化学测定MMP-9与TIMP-1蛋白表达。结果:Triol与25-OH(1 mg/L,24 h)抑制TIMP-1 mRNA及蛋白表达,对MMP-9蛋白表达无影响。结论:氧化型胆固醇可以下调血管平滑肌细胞TIMP-1基因表达。