基质金属蛋白酶、金属蛋白酶组织抑制剂在心室重构中的作用和调节

心室重构是决定心脏病患者心功能及其预后的主要因素之一 ,是心脏基质成分合成或降解代谢失平衡的结果。心脏基质在维护心脏结构和功能完整性方面起着重要的作用。基质重构引起心肌纤维化和进行性心室扩张 ,最终导致心力衰竭。在心肌中存在的能降解所有心脏基质成分的基质金属蛋白酶 (ＭＭＰｓ) ,是重构过程中心脏基质降解的主要因素。在衰竭的心脏中 ,ＭＭＰｓ活性升高导致纤维胶原降解、细胞外基质重构和进行性心室扩张。ＭＭＰｓ在转录前和转录后水平都可调节 ,而且可通过底物间的相互作用和通过内源性生理抑制剂即金属蛋白酶组织抑制剂 …     

基质金属蛋白酶抑制剂强力霉素对大鼠急性心肌梗死后左心室重构和功能的影响

目的:评价基质金属蛋白酶抑制剂强力霉素对大鼠急性心肌梗死(AMI)后左心室重构和功能的影响.方法:AMI术后24小时存活的127只雌性SD大鼠随机分成AMI组64只和强力霉素组63只[30 mg/(kg·d)],并开始给药治疗;另设30例对照作为假手术组.上述各组再随机分配,分别观察1周、2周和4周3个疗程.满疗程后均以导管法行血流动力学测定、心脏标本固定和病理分析.最终94只大鼠获完整资料.结果:梗死面积在AMI组和强力霉素组3个疗程间均无显著差异(42%～48%,P均＞0.05).与假手术组相比,AMI组的左心室舒张末压、实际和相对重量在各时间点均显著增加(P＜0.05～0.001),且左心室舒张末压在4周比1和2周时升高更显著(P均＜0.01);而左心室内压最大上升和下降速率及其校正值(左心室内压最大上升和下降速率/左心室收缩压)在4周时均显著降低(P均＜0.001).与AMI组相比,强力霉素组的左心室舒张末压在各时间点均显著降低(P＜0.05～0.001);实际和相对重量在4周时均显著减轻(P＜0.05～0.001);而左心室内压最大上升和下降速率的校正值在4周时均显著升高(P＜0.05～0.01).结论:基质金属蛋白酶抑制剂强力霉素能有效防治大鼠急性心肌梗死后左心室重构,并改善左心室收缩和舒张功能.     

基质金属蛋白酶与心肌间质重构

在心力衰竭的进展过程中，心室重构起主要作用。心室重构包括心肌实质重构和心肌间质重构，心肌间质重构是指成纤维细胞增生、纤维化以及细胞外基质胶原网的量和组成的变化。基质金属蛋白酶（MMPs）是一种能特异地降解细胞外基质成分的Zn^2 依赖的酶家族，心肌中的MMPs能够降解心脏中所有的基质成分，是心肌间质重构中基质降解的推动力量。MMPs的表达与活性受到肿瘤坏死因子-α、白介素－1β、血管紧张素Ⅱ、内皮素以及金属蛋白酶组织型抑制物等因子的调控。通过直接或间接的方法调节MMPs的活性，可以改变心肌间质重构过程，从而最终改变心力衰竭的进程。     

基质金属蛋白酶-9对斑块稳定性的影响及强力霉素的干预效果

目的 探讨基质金属蛋白酶-9(MMP-9)与大鼠动脉粥样硬化斑块稳定性的关系及强力霉素的干预效果.方法 36只雄性Wistar大鼠随机分为对照组(C组)、动脉粥样硬化组(A组)和强力霉素干预组(D组),A组和D组给予高脂饲料+维生素D3腹腔注射,D组同时予强力霉素10 mg·kg-1·d-1腹腔注射一次.于第14周确定造模成果后测量血清MMP-9、血浆超敏C反应蛋白(hs-CRP)水平,取主动脉石蜡包埋切片,HE染色,观察斑块形态,计数易损斑块数目.结果 D组血MMP-9、hs-CRP水平均低于A组(P<0.01,P<0.05),而高于C组(P<0.01);各组MMP-9与hs-CRP水平呈正相关(r=0.928,P<0.01).D组血管内膜/中膜面积比及易损斑块计数较A组均降低(P<0.05,P<0.01).结论 强力霉素可以通过抑制MMP-9活性达到稳定动脉粥样硬化斑块的作用.     

基质金属蛋白酶家族及其在心力衰竭心室重构中的作用

在心力衰竭的发展过程中常发生心室重构 ,包括心肌细胞的肥厚和细胞外基质的变化 ,后者是心室重构的重要原因。基质金属蛋白酶是一组能特异地降解细胞外基质成分的 Zn2 + 依赖的酶家族 ,在左心室的重构过程中起重要作用。     

基质金属蛋白酶及其抑制剂TIMPs在心肌间质重塑中的作用

心脏重塑是各种病因的进展性充血性心力衰竭的共同病理机制。心脏重塑不仅表现为心肌细胞的凋亡、坏死、肥大、延长和心肌肥厚 ,还表现为心肌间质纤维胶原合成和降解之间动态平衡的破坏。基质金属蛋白酶 (ｍａｔｒｉｘｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅｓ,ＭＭＰｓ)是降解细胞外基质 (ＥＣＭ)成分的最主要酶系 ,金属蛋白酶组织抑制因子 (ｔｉｓｓｕｅｉｎｈｉｂｉｔｏｒｓｏｆｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅｓ,ＴＩＭＰｓ)是基质金属蛋白酶的内源性特异性抑制剂。近年的研究发现 ,ＭＭＰｓ和ＴＩＭＰｓ在调节心肌细胞外基质的更新中…     

醛固酮受体拮抗剂对心肌梗死大鼠心肌基质金属蛋白酶及其抑制剂的影响

目的：探讨醛固酮受体桔抗剂影响心室重构的分子机制。方法：大鼠随机分为3组,假手术组、急性心肌梗死（AMI）对照组和螺内酯组,每组均6只。AMI对照组和螺内酯组通过结扎左冠状动脉前降支诱导大鼠AMI模型,螺内酯组用螺内酯进行治疗。应用RT-PCR方法测定非梗死区心肌组织中MMP-2 mRNA、TIMP-2 mRNA,用免疫组化法测定MMP-2、TIMP-2的蛋白表达。观察分析第2、7、14、21天上述指标的变化。结果：①与假手术组比较,AMI组MMP-2、MMP-2 mRNA和TIMP-2、TIMP-2 mRNA表达明显升高（P均〈0．01）;②与AMI组比较,螺内酯组MMP-2、MMP-2 mRNA表达在第7、14天及21天时分别降低17％、27％、29％和30％、33％、43％（P均〈0．01）;TIMP-2、TIMp-2 mRNA表达在第7、14天及21天时分别降低了14％、27％、35％和14％、25％、34％（P均〈0．01）。结论：心肌梗死大鼠非梗死区MMP-2、TIMP-2转录及表达活性增高,螺内酯能显著降低非梗死区MMP-2、TIMP-2转录及表达活性。     

基质金属蛋白酶及其抑制剂与心脏重构

本文介绍了基质金属蛋白酶 (MMPs )及其抑制剂新近发现的在心肌重构中的作用 ,选择性表达以及基质金属蛋白酶抑制剂的应用进展。     

罗格列酮对糖尿病大鼠心肌基质金属蛋白酶2表达的影响

目的观察罗格列酮对2型糖尿病大鼠心肌基质金属蛋白酶2(MMP-2)的影响。方法42只W istar大鼠随机分成正常对照组(n=6)和糖尿病组(n=36),糖尿病组以小剂量链脲佐菌素(25 mg/kg)腹腔注射的方法建立2型糖尿病大鼠模型。糖尿病组再随机分为罗格列酮组、格列齐特组和糖尿病对照组,分别应用罗格列酮(2 mg/kg)、格列齐特(25 mg/kg)和淀粉治疗,疗程12 w。应用透射电镜评价各组心肌超微结构,应用免疫组化方法和RT-PCR方法分别检测心肌MMP-2蛋白和mRNA表达水平。结果糖尿病组心肌出现明显的心肌重构,罗格列酮组病变较糖尿病对照组轻。糖尿病对照组心肌MMP-2蛋白和mRNA水平明显高于正常组大鼠〔(0.47±0.03)vs(0.17±0.02)和(1.14±0.09)vs(0.46±0.05),均P<0.01〕;罗格列酮组心肌MMP-2蛋白和mRNA水平明显低于糖尿病对照组〔(0.26±0.03)vs(0.47±0.03)和(0.72±0.08)vs(1.14±0.09),均P<0.05〕。结论罗格列酮能够明显改善糖尿病大鼠早期心肌重构,机制可能与抑制心肌MMP-2的表达有关。     

己酮可可碱对心肌肥厚大鼠基质金属蛋白酶2和9表达的影响

目的观察基质金属蛋白酶2和9在心肌肥厚大鼠模型中的变化,并采用己酮可可碱进行干预,以确定己酮可可碱对基质金属蛋白酶的影响及其在心肌肥厚过程中的作用。方法24只雄性SD大鼠随机分为对照组、去甲肾上腺素造模组(模型组)和去甲肾上腺素 己酮可可碱组(治疗组)。采用VG染色评价组织胶原表达,并测定心肌组织胶原含量,免疫组织化学法检测心肌组织基质金属蛋白酶2和9的蛋白表达。结果模型组大鼠发生左心室肥厚,胶原含量显著高于对照组(1.929±0.514mg/g比1.009±0.442mg/g,P<0.01);基质金属蛋白酶2和9表达(分别为131.1±9.8、125.3±4.1)显著低于对照组(P<0.01)。己酮可可碱治疗组心肌总胶原含量较模型组显著降低(1.151±0.215mg/g,P<0.01);基质中基质金属蛋白酶2和9的表达(分别为153.5±6.9、149.5±5.3)较模型组显著增高(P<0.01)。结论己酮可可碱能有效防治心肌肥厚的发生及细胞外基质重塑,这一效应可能与其降低心肌组织中基质金属蛋白酶2和9的高表达有关。     

缬沙坦对CHF患者对心功能、心室重构及基质金属蛋白酶的影响

目的 探讨缬沙坦治疗慢性心力衰竭（CHF）患者的临床效果及对患者心室重构、基质金属蛋白酶的影响。方法 选取2014年1月至2016年1月在我院进行诊治的108例CHF患者,采用SPSS 16.0软件生成随机数字表分为观察组（基础治疗 缬沙坦）、对照组（基础治疗）各54例,疗程均为2个月,对比两组患者的临床疗效、心室重构指标、血清基质金属蛋白酶（MMP）的水平变化。结果 治疗后,观察组患者的LVEF%高于对照组（P<0.05）,LVEDd、LVESd、LVMI、MWS值均低于对照组（P<0.05）,观察组患者的TIMP-1高于对照组（P<0.05）,MMP-1、MMP-9水平均低于对照组（P<0.05）;治疗后,观察组患者显效64.81%、有效33.33%、无效1.85%,对照组显效48.15%、有效46.30%、无效5.56%,两组比较差异具有统计学意义（P<0.05）。 结论 缬沙坦治疗CHF患者能进一步改善患者心功能、延缓心室重构,作用机制可能和降低血清基质金属蛋白酶有关。     

基质金属蛋白酶对大鼠心肌梗死后心室重塑的影响

目的　探讨大鼠心肌梗死后心肌间质基质金属蛋白酶 (MMPs)活性和心室重塑的关系及药物氯沙坦干预的影响。方法　Sprague Dawley(SD)大鼠 82只 ,随机分为对照组 (n =10 )、心肌梗死组 (MI组 ,n =36 )和氯沙坦组 (n =36 )。氯沙坦组予氯沙坦 5 0mg·kg-1·d-1灌胃 ,第 2周开始与MI组予异丙肾上腺素。酶谱法测定各组不同时间MMPs活性 ,氯胺T法测定胶原含量 ,免疫组化法测定I/III胶原比例 ,电镜观察心肌超微结构。结果　心肌梗死组MMP 2、MMP 9活性在各周时间点明显升高 ,胶原含量和I/III胶原比例随后升高。而氯沙坦组MMPs活性、胶原含量和I/III胶原比例较MI组显著降低。结论　大鼠心梗后间质内MMPs活性升高 ,继发胶原含量增加 ,I/III胶原比例升高 ,是心室重塑的重要原因。氯沙坦对MMPs活性的影响可能是其干预心梗后心室重塑的机制之一。     

基质金属蛋白酶和心肌梗死后心室重构

心肌梗死后心室重构是慢性心力衰竭发展的重要病理基础，延缓或阻止心室重构已成为慢性心力衰竭的主要治疗方法。基质金属蛋白酶是一组与心室胞外基质重构有关的水解酶，抑制基质金属蛋白酶的表达和活性对心室重构的防治有重要意义。     

Calcineurin and matrix protein expression in cardiac hypertrophy

In the compensatory state of human left ventricular hypertrophy (LVH), the remodeling processes in the extracellular matrix and the role of calcineurin (Cn) are not completely understood. The present work aimed to analyze the expression and activity of matrix metalloproteinases (MMPs), their endogenous inhibitors (TIMPs), and of Cn in patients with compensated LVH. By semiquantitative RT-PCR, Western blotting, and gelatine zymography, we determined mRNA, protein, and/or enzyme activity levels of MMPs, TIMPs, atrial natriuretic peptide (ANP), Cn subunits, and of the modulatory calcineurin-interacting protein (MCIP) 1. Myocardial samples from patients showing severe aortic stenosis, normal ejection fraction, and compensated LVH were compared with autopsy samples from healthy hearts. LVH patients showed upregulation of CnA-β mRNA but downregulation of both CnB-α mRNA and protein. Total Cn activity (as determined through NF-AT phosphorylation and MCIP1 mRNA expression) was unchanged. There were no differences in gene expression and activities of MMP-2, MMP-9, and of TIMPs 1–4 between LVH patients and controls. As expected, ANP mRNA expression was high in LVH patients. We propose a prominent role for CnB in controlling Cn activity in compensated LVH. At this stage of the disease, MMP and TIMP activities are balanced. Drs. Grammer and Bleiziffer contributed equally to the study Returned for 1st revision: 23 February 2006 1. revision received: 8 April 2006     

阿托伐他汀在心肌细胞肥大治疗中的作用

大量研究表明阿托伐他汀可干预心室重塑的形成和发展.应用阿托伐他汀能从不同途径发挥独特的心血管保护效应.本文从心肌细胞肥大这个角度阐述阿托伐他汀对心室重塑的影响.     

Anti-collagenolytic mechanism of action of doxycycline treatment in rheumatoid arthritis

Tetracyclines exert, independently of their anti-microbial activity, anti-collagenolytic effects by inhibiting activities of human interstitial collagenases and by preventing the oxidative activation of latent pro-collagenases. We tested the clinical response to a 3-month doxycycline in concert with collagenase activity in 12 rheumatoid arthritis (RA) patients. Patients received 150 mg/day of doxycycline for 3 months. Clinical assessments at zero, six and 12 weeks comprised classification of the functional class, joint score index, Hb, CRP, ESR, health assessment questionnaire, visual analogue scale (VAS) of pain, pain disability index, comprehensible psychopathological rating scale (CPRS), SDS-PAGE laser densitometric collagenase activity measurements and Western blots. Significant reductions were seen in joint score index (P<0.01), pain VAS (P<0.05) and some CPRS parameters. Furthermore, collagenase activities measured from saliva by quantitative SDS-PAGE electrophoresis were significantly reduced during the 12-week intervention (P<0.01). Western blots demonstrated intact 75–80 kDa enzyme protein (classic neutrophil collagenase), but also a newly discovered mesenchymal, less glycosylated 40–55 kDa MMP-8 subtype of fibroblast/chondrocytic origin. These results indicate that the documented favourable clinical response may in part be due to in vivo inhibition of classic neutrophil and mesenchymal collagenase/MMP-8 activities produced by doxycycline. This anti-collagenolytic doxycycline effects is mediated through inhibition of the enzyme activity and not through degradation of the enzyme, which may have contributed to the reportedly reduced tissue destruction, as has been seen in clinical studies concerning RA as well as reactive arthritis. Received: 20 May 1997 / Accepted: 9 October 1997     

基质金属蛋白酶与慢性阻塞性肺疾病形成机制的关系

基质金属蛋白酶是一类在结构和功能上具有相似性的锌（Zn^2＋）钙（Ca^2＋）离子依赖性蛋白酶超家族。能降解肺组织细胞外基质（ECM）中的多种蛋白成分，导致ECM合成与降解失衡，并与细胞因子相互作用，在慢性阻塞性肺疾病的易感性，炎性反应和气道重构的过程中发挥重要作用。     

Role of FAK signaling in chagasic cardiac hypertrophy

Cardiac hypertrophy and dysfunction are a significant complication of chronic Chagas disease, with heart failure, stroke, and sudden death related to disease progression. Thus, understanding the signaling pathways involved in the chagasic cardiac hypertrophy may provide potential targets for pharmacological therapy. Herein, we investigated the implication of focal adhesion kinase (FAK) signaling pathway in triggering hypertrophic phenotype during acute and chronic T. cruzi infection. C57BL/6 mice infected with T. cruzi (Brazil strain) were evaluated for electrocardiographic (ECG) changes, plasma levels of endothelin-1 (ET-1) and activation of signaling pathways involved in cardiac hypertrophy, including FAK and ERK1/2, as well as expression of hypertrophy marker and components of the extracellular matrix in the different stages of T. cruzi infection (60–210 dpi). Heart dysfunction, evidenced by prolonged PR interval and decrease in heart rates in ECG tracing, was associated with high plasma ET-1 level, extracellular matrix remodeling and FAK signaling activation. Upregulation of both FAK tyrosine 397 (FAK-Y397) and serine 910 (FAK-S910) residues phosphorylation as well as ERK1/2 activation, lead to an enhancement of atrial natriuretic peptide gene expression in chronic infection. Our findings highlight FAK-ERK1/2 signaling as a regulator of cardiac hypertrophy in Trypanosoma cruzi infection. Both mechanical stress, induced by cardiac extracellular matrix (ECM) augment and cardiac overload, and ET-1 stimuli orchestrated FAK signaling activation with subsequent activation of the fetal cardiac gene program in the chronic phase of infection, highlighting FAK as an attractive target for Chagas disease therapy.     

Role of matrix metalloproteinases in cholestasis and hepatic ischemia/reperfusion injury:A review

Matrix metalloproteinases(MMPs) are a family ofproteases using zinc-dependent catalysis to break down extracellular matrix(ECM) components, allowing cell movement and tissue reorganization. Like many other proteases, MMPs are produced as zymogens, an inactive form, which are activated after their release from cells. Hepatic ischemia/reperfusion(I/R) is associated with MMP activation and release, with profound effects on tissue integrity: their inappropriate, prolonged or excessive expression has harmful consequences for the liver. Kupffer cells and hepatic stellate cells can secrete MMPs though sinusoidal endothelial cells are a further source of MMPs. After liver transplantation, biliary complications are mainly attributable to cholangiocytes, which, compared with hepatocytes, are particularly susceptible to injury and ultimately a major cause of increased graft dysfunction and patient morbidity. This paper focuses on liver I/R injury and cholestasis and reviews factors and mechanisms involved in MMP activation together with synthetic compounds used in their regulation. In this respect, recent data have demonstrated that the role of MMPs during I/R may go beyond the mere destruction of the ECM and may be much more complex than previously thought. We thus discuss the role of MMPs as an important factor in cholestasis associated with I/R injury.