Improved balance between TIMP-3 and MMP-9 after regional myocardial ischemia-reperfusion during AT1 receptor blockade

BACKGROUND: Angiotensin II (AngII) modulates the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), and AngII type 1 receptor (AT1R) blockers (ARBs) limit left ventricular (LV) dysfunction and remodeling after acute ischemia-reperfusion (IR). Whether ARBs improve TIMP/MMP balance during IR has not been determined. METHODS AND RESULTS: We measured hemodynamics, LV function, MMP-2 and MMP-9, and TIMP-3 and TIMP-4 in the ischemic zone (IZ) and nonischemic zone (NIZ) after in vivo IR (90 minutes anterior ischemia; 120 minutes reperfusion) in 28 dogs that were randomized to sham, IR controls, and IR plus the ARB valsartan. In controls, IR induced LV dysfunction, infarction, and IZ remodeling; increased MMP-9 and decreased TIMP-3 in the IZ compared with the NIZ (low TIMP-3/MMP-9 ratio); and did not change MMP-2 or TIMP-4. Compared with controls, valsartan (1) limited LV dysfunction, infarct size, and IZ remodeling; (2) increased MMP-2 and MMP-9 and TIMP-3 and -4 in the NIZ; and (3) increased TIMP-3 and the TIMP-3/MMP-9 ratio in the IZ, but did not change MMP-2 and TIMP-4. CONCLUSION: Valsartan-induced cardioprotection after IR is associated with enhanced TIMP-3 expression and improved TIMP-3/MMP-9 balance in the in vivo dog model.     

Increased circulating matrix metalloproteinase-2 in patients with hypertrophic cardiomyopathy with systolic dysfunction.

BACKGROUND: Some patients with hypertrophic cardiomyopathy (HCM) develop left ventricular (LV) wall thinning associated with LV dilatation and systolic dysfunction. Recently, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were reported to be involved in ventricular remodeling, however, little is known about MMPs and TIMPs in patients with HCM. METHODS AND RESULTS: Enzyme-linked immunoassays were used to measure the plasma concentrations of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 in 11 patients with HCM accompanied by systolic dysfunction (fractional shortening (FS) <25%, group A), 17 patients with HCM who had preserved systolic function (FS> or =25%, group B), and 50 age-matched clinically healthy control subjects (mean age: 57 years). The concentration of MMP-2 in group A was significantly higher than in group B and the control subjects (1,124 +/- 84, 792 +/- 49, 809 +/- 26 ng/ml, respectively), whereas there was no significant difference between group B and the control subjects. MMP-2 concentrations significantly increased as the New York Heart Association functional class increased in patients with HCM. TIMP-2 was also significantly higher in group A patients than in group B and the control subjects (45.3 +/- 4.7, 34.6 +/- 2.2, 33.7 +/- 1.8 ng/ml, respectively), but there was no difference between group B and control subjects. TIMP-1 was significantly higher in HCM patients than in control subjects. MMP-3 and MMP-9 concentrations did not differ among the 3 groups. Both MMP-2 and TIMP-2 correlated significantly with FS and LV dimension, negatively and positively, respectively. CONCLUSIONS: These results suggest that changes in the release and activity of MMP-2 and TIMP-2 may be associated with the mechanisms responsible for cardiac remodeling in patients with HCM.     

Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase-type 1 (TIMP-1) on left ventricular geometry and function in mice

Alterations in the expression and activity of the matrix metalloproteinases (MMPs) and the tissue inhibitors of the MMPs (TIMPs) have been implicated in tissue remodeling in a number of disease states. One of the better characterized TIMPs, TIMP-1, has been shown to bind to active MMPs and to regulate the MMP activational process. The goal of this study was to determine whether deletion of the TIMP-1 gene in mice, which in turn would remove TIMP-1 expression in LV myocardium, would produce time-dependent effects on LV geometry and function. Age-matched sibling mice (129Sv) deficient in the TIMP-1 gene (TIMP-1 knock-out (TIMP-1 KO), n=10) and wild-type mice (n=10) underwent comparative echocardiographic studies at 1 and 4 months of age. LV catheterization studies were performed at 4 months and the LV harvested for histomorphometric studies. LV end-diastolic volume and mass increased (18+/-4 and 38+/-3%, respectively, P<0.05) at 4 months in the TIMP-1 KO group; a significant increase compared to wild-type controls (P<0.05). At 4 months, LV and end-diastolic wall stress was increased by over two-fold in the TIMP-1 KO compared to wild type (P<0.05). However, LV systolic pressure and ejection performance were unchanged in the two groups of mice. LV myocyte cross-sectional area was unchanged in the TIMP-1 KO mice compared to controls, but myocardial fibrillar collagen content was reduced. Changes in LV geometry occurred in TIMP-1 deficient mice and these results suggest that constitutive TIMP-1 expression participates in the maintenance of normal LV myocardial structure.     

基质金属蛋白酶在心肌肥厚大鼠中的作用及强力霉素的干预效果

目的:观察心肌肥厚大鼠模型中基质金属蛋白酶(MMP)-2,MMP-9及其抑制剂(TIMP-1)的表达及强力霉素干预后对其影响。方法:24只大鼠随机分为对照组(A组,只给予0.9%氯化钠溶液腹腔注射);造模组(B组)和药物干预组(C组)均用去甲肾上腺素1.06mg/kg腹腔注射,bid,注射15d,建立大鼠心肌肥厚模型,C组造模同时给予强力霉素10mg/kg腹腔注射,qd,给药15d。全部动物于给药后16d处死测定全心质量指数、左室质量指数、心肌胶原含量、心肌组织MMP-2,MMP-9,TIMP-1、心肌胶原容积分数(CVF)。结果:与A组比较,B组全心质量指数、左室质量指数、MMP-2、MMP-9阳性表达率、心肌胶原含量及CVF均明显增加(P<0.05),TIMP-1阳性表达率明显降低(P<0.05)。与B组比较,C组全心质量指数、左室质量指数、MMP-2、MMP-9阳性表达率、心肌胶原含量及CVF均明显降低(P<0.05),TIMP-1阳性表达率增加(P<0.05)。结论:去甲肾上腺素诱导的心肌肥厚大鼠MMPs/TIMPs系统平衡破坏,使基质胶原降解与合成平衡破坏,从而导致心室重构。强力霉素可通过抑制MMP来逆转心室重构。     

基质金属蛋白酶在阿霉素心肌病左室重构中的表达与意义

目的:研究基质金属蛋白酶(MMPs)及金属蛋白酶组织抑制因子(TIMPs)在阿霉素心肌病(ADR DCM)大鼠左室心肌中的表达与意义。方法:雄性Wistar大鼠分两组:正常对照组(n=10)和ADR DCM组(n =25)。ADR DCM模型建立方法:阿霉素2.5mg/kg,尾静脉注射,每周1次,连续10周。12周时进行超声检测 评价其心功能,硫代巴比妥酸法检测丙二醛(MDA)含量,逆转录 聚合酶链反应、Western印迹分析检测MMP 2、 MMP 9及TIMP 1的表达。结果:ADR DCM组大鼠死亡率40%,左室舒张末期内径及收缩末期内径增加,左室 短轴缩短率明显下降,MDA含量增加(P<0.01)。ADR DCM组大鼠左室心肌MMP 2、MMP 9mRNA及蛋白 水平表达较正常对照组明显升高(P<0.01),而TIMP 1的表达在两组间均无统计学意义(P>0.05)。结论: ADR DCM左室心肌MMPs表达上调,MMPs可能参与ADR DCM左室重构和心力衰竭的发生发展。     

Role of fibroblast growth factor-2 in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human intestinal myofibroblasts

BACKGROUND AND AIMS: The coordinated expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) plays a crucial role in tissue remodeling. We investigated the effects of fibroblast growth factor (FGF)-2 on the secretion of MMPs and TIMPs in human intestinal subepithelial myofibroblasts (SEMFs). METHODS: The secretion of MMP-s and TIMPs was determined by ELISA or Western blotting. The mRNA expression of MMPs and TIMPs was assessed by Northern blotting. The activating protein (AP)-1-DNA binding activity was evaluated by electrophoretic gel mobility shift assays (EMSA). RESULTS: Unstimulated intestinal SEMFs constitutively secreted MMP-2 and TIMP-2. FGF-2 stimulated MMP-1, MMP-3 and TIMP-1 secretion, but did not affect MMP-2 or TIMP-2 secretion. FGF-2 induced AP-1-DNA binding activity, and the c-Jun/AP-1 inhibitor curcumin attenuated the FGF-2-induced MMP-1, -3 and TIMP-1 mRNA expression. Mitogen-activated protein (MAP) kinase inhibitors (U0126 and PD098059) also blocked the MMP-1, -3 and TIMP-1 secretion. Furthermore, FGF-2 dose-dependently induced FGF-2 mRNA expression in these cells. CONCLUSIONS: FGF-2 may be one of important regulatory factors for extracellular matrix turnover via a modulation of MMP and TIMP secretion from SEMFs.     

Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats

OBJECTIVES: We sought to elucidate how the local activation of matrix metalloproteinases (MMPs) is balanced by that of the endogenous tissue inhibitors of MMP (TIMPs) during left ventricular (LV) remodeling. BACKGROUND: Although it is known that the extracellular matrix (ECM) must be altered during LV remodeling, its local regulation has not been fully elucidated. METHODS: In Dahl salt-sensitive rats with hypertension, in which a stage of concentric, compensated left ventricular hypertrophy (LVH) at 11 weeks is followed by a distinct stage of congestive heart failure (CHF) with LV enlargement and dysfunction at 17 weeks, we determined protein and messenger ribonucleic acid (mRNA) levels of LV myocardial TIMP-2 and -4 and MMP-2, as well as their concomitant activities. RESULTS: No changes were found at the LVH stage. However, during the transition to CHF, TIMP-2 and -4 activities, protein and mRNA levels were all sharply increased. At the same time, the MMP-2 mRNA and protein levels and activities, as determined by gelatin zymography, as well as by an antibody capture assay, showed a substantial increase during the transition to CHF. The net MMP activities were closely related to increases in LV diameter (r = 0.763) and to systolic wall stress (r = 0.858) in vivo. CONCLUSIONS: Both TIMPs and MMP-2 remained inactive during hypertrophy, per se; they were activated during the transition to CHF. At this time, the activation of MMP-2 surpassed that of TIMPs, possibly resulting in ECM breakdown and progression of LV enlargement.     

Plasma matrix metalloproteinase-9 level is correlated with left ventricular volumes and ejection fraction in patients with heart failure

BackgroundMatrix metalloproteinases (MMPs) can alter myocardial extracellular matrix and thereby contribute to adverse ventricular remodeling in progressive heart failure (HF). We hypothesized that increased plasma MMP levels correlate with increased left ventricular (LV) volumes and reduced LV ejection fraction (LVEF) in patients with HF.Methods and ResultsIn the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, patients with symptomatic HF and LVEF <0.40 were randomized to receive various combinations of therapies with candesartan, enalapril, and metoprolol CR. Left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and LVEF were determined by radionuclide angiography at baseline and at Week 43. Baseline and Week 43 plasma MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured by enzyme-linked immunosorbent assay in 184 patients in this substudy. At baseline, plasma MMP-9 correlated positively with ESV (Spearman's rank correlation coefficient ρ = 0.17, P = .02) and negatively with LVEF (ρ = –0.18, P = .01). After 43 weeks, LVEF, EDV, and ESV increased significantly (all P < .01); MMP-2 level increased (P = .01), but MMP-9 and TIMP-1 levels did not change significantly overall in the study population. Temporal changes in MMP-9 level were inversely correlated with changes in LVEF (ρ = –0.16, P = .04). In multivariable analysis adjusting for clinical characteristics and treatment, a smaller proportional change in MMP-9 level after 43 weeks (below versus above median) predicted a concurrent improvement in LVEF (odds ratio = 2.35, 95% CI 1.24–4.46; P < .01). Similar relationships for MMP-2 and TIMP-1 were not observed.ConclusionsElevated plasma MMP-9 levels correlated with lower LVEF and higher ESV, whereas increasing MMP-9 levels are associated with a concurrent deterioration of LV function. These findings suggest that monitoring of plasma markers of myocardial matrix remodeling may provide important prognostic information with respect to ongoing adverse LV remodeling in HF patients.     

Matrix metalloprotease activity is enhanced in the compensated but not in the decompensated phase of pressure overload hypertrophy

BACKGROUND: During the transition of pressure overload hypertrophy (POH) to heart failure (HF) there is intense interstitial cardiac remodeling, characterized by a complex balance between collagen deposition and degradation by matrix metalloproteases (MMPs). This study was aimed at investigating the process of cardiac remodeling during the different phases of the transition of POH to HF. METHODS: Guinea pigs underwent thoracic descending aortic banding or sham operation. Twelve weeks after surgery, left-ventricular (LV) end-diastolic internal dimension and ventricular systolic pressure were measured by combined M-mode echocardiography and micromanometer cathetherization. The MMP activity, tissue-specific MMP inhibitors (TIMPs), and collagen fraction were evaluated in LV tissue samples by zymography, ELISA, and computer-aided analysis, respectively. RESULTS: Banded animals were divided by lung weight values into either compensated left-ventricular hypertrophy (LVH) or HF groups, as compared with sham-operated controls. All HF animals exhibited a restrictive pattern of Doppler transmitral inflow, indicative of diastolic dysfunction, and developed lung congestion. Compensated LVH was associated with increased MMP-2 activity, which was blunted after transition to HF, at a time when TIMP-2 levels and collagen deposition were increased. CONCLUSIONS: The cardiac remodeling process that accompanies the development of POH is a phase-dependent process associated with progressive deterioration of cardiac function.     

Matrix metalloproteinase abundance in human myocardial fibroblasts: effects of sustained pharmacologic matrix metalloproteinase inhibition

BACKGROUND: A cause-effect relationship has been established between matrix metalloproteinases (MMPs) and left ventricular (LV) myocardial remodeling through the use of pharmacologic MMP inhibitors. However, the direct effects of MMP inhibition on MMPs and endogenous tissue inhibitors of metalloproteinases (TIMPs) in LV human myocardial fibroblasts (LVHMFs) remain unknown. This study measured MMP-2, MMP-9, MMP-13, MT1-MMP, and TIMP-1 release in LVHMFs. METHODS AND RESULTS: LVHMF cultures were established from six individual patients (passages 2-5) and incubated with and without the broad-spectrum MMP inhibitor PD166793 (100 microM) for 12-36 h. While PD166793 did not influence MMP-2 release, MMP-9 levels based on substrate zymography increased at 36 h by over 30% (P < 0.05). TIMP-1 levels increased in a time-dependent manner with no effect from PD166793 incubation. However, the MMP-9/TIMP-1 ratio was increased by over 20% from time-matched values following 12-36 h of exposure to PD166793 (P < 0.05). Similar results obtained after incubation of LVHMF cultures with the broad-spectrum MMP inhibitor Batimastat (BB-94) suggest that these observations are due to a general class effect of broad-spectrum MMP inhibitors. CONCLUSIONS: This study is the first to demonstrate that a selective induction and release of an MMP species occurs with sustained exposure to pharmacologic MMP inhibition in LVHMFs. These observations may have particular importance with respect to controlling this proteolytic system in the context of LV myocardial remodeling.     

Plasma matrix metalloproteinase and inhibitor profiles in patients with heart failure

BACKGROUND: Changes in myocardial matrix metalloproteinases (MMPs) and the inhibitors of MMPs (TIMPs) have been demonstrated in congestive heart failure (CHF). The first objective of this study was to measure plasma profiles of MMPs and TIMPs in CHF patients (n = 24; 62 +/- 3 years; left ventricular ejection fraction [LVEF] = 24 +/- 2%) and age-matched nonfailing patients (n = 48; 63 +/- 2 years; LVEF >/= 55%). Cytokines such as tumor necrosis factor (TNF)-alpha can induce MMP expression in vitro. The second objective of this study was to determine the relationship between soluble TNF-alpha receptors (TNFR1; TNFR2) and MMP plasma profiles. METHODS AND RESULTS: Plasma levels of MMP-2, MMP-9, MMP-8, TIMP-1, TIMP-2, TNF-alpha, TNFR1, and TNFR2 were measured by enzyme-linked immunosorbent assay kits. Plasma MMP-9 levels were increased in CHF patients (25 +/- 6 versus 72 +/- 15 ng/mL, P <.05). Interestingly, plasma levels of MMP-8 were decreased in CHF patients (16 +/- 2 versus 9 +/- 2 ng/mL, P <.05). The MMP-9/TIMP-1 ratio was increased by 3-fold, whereas the MMP-9/TIMP-2 ratio was increased by 16-fold in CHF patients (both P <.05). With a 48-week follow-up in CHF patients, an absolute reduction in plasma TNFR1 from baseline was accompanied by reduced MMP-9 levels (-30 +/- 16 ng/mL; P =.058), whereas stable or increased plasma TNFR1 resulted in persistently elevated MMP-9 levels. CONCLUSIONS: The unique findings of this study were 2-fold. First, a discordant change in plasma MMP and TIMP levels occurred in CHF patients. Second, changes in cytokine activity were related to changes in plasma MMP levels. These changes in MMP/TIMP levels likely reflect the progression and/or acceleration of the LV remodeling process in CHF. Thus serial measurements of plasma MMP/TIMP levels may hold diagnostic/prognostic significance in CHF patients.     

Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target

A fundamental structural event in the progression of heart failure due to dilated cardiomyopathy is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) are an endogenous family of enzymes which contribute to matrix remodeling in several disease states. The goal of this report is to summarize recent findings regarding the myocardial MMP system and the relation to matrix remodeling in the failing heart. In both experimental and clinical forms of dilated cardiomyopathy (DCM), increased expression of certain species of myocardial MMPs have been demonstrated. Specifically, increased myocardial levels of the gelatinase, MMP-9 has been identified in both ischemic and non-ischemic forms of human DCM. In addition, stromelysin or MMP-3 increased by over four-fold in DCM. The increased levels of MMP-3 in DCM may have particular importance since this MMP degrades a wide range of extracellular proteins and can activate other MMPs. In normal human LV myocardium, the membrane type 1 MMP (MT1-MMP) was detected. These MT-MMPs may provide important sites for local MMP activation within the myocardium. In a pacing model of LV failure, MMP expression and activity increased early and were temporally associated with LV myocardial matrix remodeling. Using a broad-spectrum pharmacological MMP inhibitor in this pacing model, the degree of LV dilation was attenuated and associated with an improvement in LV pump function. Thus, increased LV myocardial MMP expression and activity are contributory factors in the LV remodeling process in cardiomyopathic disease states. Regulation of myocardial MMP expression and activity may be an important therapeutic target for controlling myocardial matrix remodeling in the setting of developing heart failure.     

Ventricular remodeling and function: Insights using murine echocardiography

Extracellular matrix disturbances play an important role in the development of ventricular remodeling and failure. Genetically modified mice with abnormalities in the synthesis and degradation of extracellular matrix have been generated, in particular mice with deletion or overexpression of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). Echocardiography is ideally suited to serially evaluate left ventricular (LV) size and function, thus defining the progression of LV remodeling and failure. This Review describes the echocardiographic parameters that may provide insights into the development of ventricular remodeling and heart failure. The application of echocardiography to study LV remodeling and function after myocardial infarction and LV pressure-overload in wild-type mice and mice deficient or overexpressing MMPs or TIMPs is then detailed. Finally, using the example of mice deficient in nitric oxide synthase 3, a cautionary example is given illustrating discrepancies between the cardiac echocardiographic phenotype and modifications of the extracellular matrix.     

Selective induction of matrix metalloproteinases and tissue inhibitor of metalloproteinases in atrial and ventricular myocardium in patients with atrial fibrillation

Atrial fibrillation (AF) produces changes in atrial structure and extracellular matrix composition, which is regulated by matrix metalloproteinases (MMPs). Moreover, AF often occurs in the setting of congestive heart failure (CHF), which also affects MMPs. Whether changes in MMPs or the tissue inhibitors of metalloproteinases (TIMPs) within atrial and ventricular myocardium are differentially regulated with AF remains unclear. Myocardium from the walls of the right atrium, right ventricle, left atrium, and left ventricle was obtained from the explanted hearts of 43 patients with end-stage CHF. AF was present in 23 patients (duration 1 to 84 months). The remaining 20 patients served as non-AF controls. The groups were well matched clinically, but left atrial (LA) size was increased in the AF cohort (5.5 +/- 0.8 vs 4.9 +/- 0.7 cm, p <0.05). Myocardial collagen content and levels of MMP-1, -2, -8, -9, -13, and -14, and TIMP-1, -2, -3, and TIMP-4 were determined. With AF, collagen content was greater within the atrial myocardium but less in the ventricular myocardium. There were chamber-specific differences in MMPs and TIMPs with AF. For example, MMP-1 in the right atrium and MMP-9 in the left atrium were greater with AF. TIMP-3 levels were greater in the right ventricle, left atrium, and left ventricle. Although total LA collagen was positively correlated with AF duration (r = 0.49, p <0.03), there was an inverse relation between soluble collagen I and AF duration (n = 6, r = -0.84, p <0.04). In conclusion, AF is associated with chamber-specific alterations in myocardial collagen content and MMP and TIMP levels, indicative of differential remodeling and altered collagen metabolism. Differences in MMP and TIMP profiles may provide diagnostic and mechanistic insights into the pathogenesis of AF with CHF.     

钙网蛋白及基质金属蛋白酶在扩张型心肌病发病机制中的作用

目的 探讨扩张型心肌病与钙网蛋白（Calreticulin）、基质金属蛋白酶（MMPs）家族成员MMP-2和MMP-9之间的关系,为扩张型心肌病的预防和治疗提供理论论据.方法 试验分两组：扩张型心肌病组和对照组.分别收集14例扩张型心肌病患者及14例对照组全血及临床资料（年龄,性别,左房、右房、左室、右室舒张末期内径及左室射血分数等）,提取血浆,通过蛋白免疫印迹法（western blotting）测定血浆钙网蛋白的表达水平,通过明胶酶谱法（Gelatin-PAGE）检测各标本血浆中MMP-2和MMP-9活性.结果 ①扩张型心肌病组与对照组比较,两组间左房、左室舒张末期内径、左室射血分数和MMP-9活性的差异有统计学意义.②在扩张型心肌病组中,MMP-9活性与左室射血分数呈负相关（r＝-0.590,P＜0.05）,与左室舒张末径呈正相关（非正态分布等级相关：r＝0.396,P＜0.05）,但与左房、右房、右室舒张末径和室间隔厚度均无相关关系.对照组中,MMP-9与左房、右房、左室、右室舒张末径和室间隔厚度均无相关关系.③两组比较,MMP-2活性差异无统计学意义,与左房、右房、左室、右室舒张末径,左室射血分数和室间隔厚度之间均无相关关系.④钙网蛋白在扩张型心肌病组的表达升高,但与对照组相比,两者间的表达水平差异无统计学意义（P＞0.05）.结论 ①MMP-9在扩张型心肌病患者左室重构中起重要作用,MMP-9的活性可作为评估心功能情况的参考指标之一.②钙网蛋白在扩张型心肌病病理过程中未直接参与其疾病发展,但未排除通过其他途径作用于该病理过程.     

Profile and localization of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in human heart valves

BACKGROUND AND AIMS OF THE STUDY: Tissue turnover is one of many factors involved in the operational longevity of heart valves. An understanding of how valves remodel their matrix in response to the hemodynamic environment in health and disease is crucial to the design and biological responsiveness of tissue-engineered valve substitutes. Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in matrix remodeling in several tissues, and include interstitial collagenase (MMP-1, MMP-13), the gelatinases (MMP-2, MMP-9) and stromelysin (MMP-3). METHODS: Expression of MMPs and their tissue inhibitors (TIMPs) in human aortic, mitral, tricuspid and pulmonary valves from unused donor or transplant recipient hearts was determined by immunohistochemical staining using antibodies against human MMP-1, MMP-2, MMP-3 and MMP-9 and their inhibitors TIMP-1, TIMP-2, TIMP-3. Cell identification was achieved using antibodies against CD31(endothelial cells), smooth muscle alpha-actin (microfilaments) and CD68 (macrophages). RESULTS: MMP-1 was expressed in all valves, whereas MMP-2 was only expressed in aortic and pulmonary leaflets. MMP-3 and MMP-9 were not expressed. TIMP-1 and TIMP-2 were expressed in all leaflets, whereas TIMP-3 was observed only in tricuspid leaflets. CONCLUSION: Valves have a specific pattern of expression of MMPs and TIMPs, which appears to vary in different heart valves. The functional implications and central mechanisms responsible require further study. These findings have important implications in understanding the dynamic nature of valve remodeling and in aiding the development of tissue-engineered valves.     

MMPs与早期行PCI的NSTEMI患者左室重构相关

目的: 探讨早期行冠状动脉介入治疗（PCI）的非ST段抬高型心肌梗死（NSTEMI）患者血浆中金属基质蛋白酶（MMPs）的时间变化规律及与心肌梗死（MI）后左心室重构的相关性。方法: 成功随访12个月的早期行PCI的NSTEMI患者126例,于入院即刻、发病后2 d、4 d、2周、4周抽取外周静脉血,ELISA检测血浆中MMP-2和MMP-9的浓度。PCI术后患者临床随访12个月,对比入院时及术后12个月心脏超声图,分析左室舒张末期容积（LVEDV）和左室射血分数（LVEF）的变化及与MMPs的相关关系。结果: ① MI后2周的时间内,血浆中MMP-2的浓度随着MI时间的延长而不断升高,其后MMP-2的浓度开始下降;MMP-9的浓度在MI后4 d时达到最高,其后MMP-9浓度开始明显下降。②同入院时相比,MI后12个月后LVEDV明显扩大,完成随访的患者LVEDV扩大(11±4) ml。LVEF明显降低,降低(9±3)%。 MI后2 d时的MMP-9的浓度与ΔLVEDV呈正相关,与ΔLVEF的相关关系不明显。4 d时的MMP-9值与12个月后的ΔLVEDV和ΔLVEF呈正相关;MI后2周和4周MMP-2的浓度与12个月后的ΔLVEDV和ΔLVEF呈正相关。结论: NSTEMI患者MI后4 d的MMP-9和2周的MMP-2浓度与短期内左心室重构及左心室功能具有明显相关性。     

Significance of cell-surface expression of matrix metalloproteinases and their inhibitors on gastric epithelium and infiltrating mucosal lymphocytes in progression of Helicobacter pylori-associated gastritis

BACKGROUND: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) have recently been shown to be important in tissue breakdown and remodeling in gut with inflammatory bowel disease. The role of MMPs and TIMPs remains largely unexplored in Helicobacter pylori-associated gastritis (HAG). The aim of this study was to investigate the expression of these proteolytic enzymes in HAG. METHODS: Cell-surface or/and intracellular expression of MMP-2, 7, 9 and MT1-MMP and TIMPs (TIMP-2 and -4) was determined in gastric epithelium and infiltrative mucosal lymphocytes (IML) in single endoscopic biopsies from H. pylori-infected (n = 25) and uninfected (n = 15) patients. The quantitative analysis was based on the percentage of positive cells detected by flow cytometry. RESULTS: Secreted MMPs and TIMPs as well as membrane type 1-MMP were shown to be localized mainly on the cell surface of both epithelial cells and IML in HAG. H. pylori significantly up-regulated the cell-surface expression not only of MMPs, but also of TIMPs on IML within tissues. The expression of these molecules on IML was correlated with the grade of gastritis. CONCLUSIONS: MMPs and TIMPs expressed on gastric epithelium and H. pylori-antigen(s)-stimulated IML may be implicated in mucosal degradation and remodeling of the stomach. These might contribute to the pathogenesis and progression of atrophy and intestinal metaplasia of gastric mucosa.