Plasma Tissue Inhibitor Of Matrix Metalloproteinase-1 Research Articles

Relationship of myocardial fibrosis markers with glomerular filtration rate in patients with arterial hypertension

Abstract Funding Acknowledgements Type of funding sources: None. Background. Renal damage in arterial hypertension is considered among the typical damage variants of target organs such as heart, blood vessels and brain. One of the complications of arterial hypertension is nephrosclerosis. Developing quite gradually, arterial hypertension kidney damage goes unnoticed for a long time because clinically it does not cause the patient any discomfort. The most accessible and objective way to assess renal function is to calculate glomerular filtration rate (GFR). Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is a protein that is a natural inhibitor of metalloproteinases and forms complexes with matrix metalloproteinase-1 and other metalloproteinases, irreversibly inhibiting their activity. Many studies have demonstrated that TIMP-1 can be considered a serum marker of myocardial and vascular fibrosis Aim of the study. To assess the relationship between GFR and plasma TIMP-1 concentration in patients with arterial hypertension. Materials and Methods. 144 patients (87 men, 67 women) with arterial hypertension with preserved systolic function were examined, mean age was 52.45 ± 4.81 years, duration of AH was 4.82 ± 2.63 years. Calculation of GFR was carried out using the MDRD formula. Tissue matrix metalloproteinase-1 inhibitor concentrations were measured with DSL kit (USA). The reference values were 92-116 ng/ml. The patients were divided into 3 groups depending on GFR: group 1 - GFR over 90 ml/min/1.73m2 (n = 59), group 2 - GFR 60-90 ml/min/1.73m2 (n = 63), group 3 - GFR under 60 ml/min/1.73m2 (n = 22). Results. The highest level of TIMP-1 (481.9 ± 106.4 ng/ml) was found in Group 3 patients (GFR <60 ml/min/1.73m2). The level of TIMP-1 in Group 3 was statistically significantly higher than in patients of Group 1 (p < 0.0001) and Group 2 (p < 0.0001). In group 2 (GFR 60-90 ml/min/1.73m2) the level of TIMP-1 (330.5 ± 108.3 ng/ml) was higher than in group 1 (297.6 ± 104.9 ng/ml), but the difference was not statistically significant (p = 0.091). The correlation analysis revealed a negative association of plasma TIMP-1 level and GFR in patients with arterial hypertension, i.e. the higher TIMP-1, the lower glomerular filtration rate (r=-0.37, p = 0.0001). Conclusions. The increased concentration of TIMP-1 in the blood of patients with arterial hypertension is evidence of increasing fibrosis in the heart and vessels, leading to the emergence and progression of renal dysfunction.

The Development of Translational Biomarkers as a Tool for Improving the Understanding, Diagnosis and Treatment of Chronic Neuropathic Pain

Chronic neuropathic pain (CNP) is one of the most significant unmet clinical needs in modern medicine. Alongside the lack of effective treatments, there is a great deficit in the availability of objective diagnostic methods to reliably facilitate an accurate diagnosis. We therefore aimed to determine the feasibility of a simple diagnostic test by analysing differentially expressed genes in the blood of patients diagnosed with CNP of the lower back and compared to healthy human controls. Refinement of microarray expression data was performed using correlation analysis with 3900 human 2-colour microarray experiments. Selected genes were analysed in the dorsal horn of Sprague–Dawley rats after L5 spinal nerve ligation (SNL), using qRT-PCR and ddPCR, to determine possible associations with pathophysiological mechanisms underpinning CNP and whether they represent translational biomarkers of CNP. We found that of the 15 potential biomarkers identified, tissue inhibitor of matrix metalloproteinase-1 (TIMP1) gene expression was upregulated in chronic neuropathic lower back pain (CNBP) (p = 0.0049) which positively correlated (R = 0.68, p = ≤0.05) with increased plasma TIMP1 levels in this group (p = 0.0433). Moreover, plasma TIMP1 was also significantly upregulated in CNBP than chronic inflammatory lower back pain (p = 0.0272). In the SNL model, upregulation of the Timp1 gene was also observed (p = 0.0058) alongside a strong trend for the upregulation of melanocortin 1 receptor (p = 0.0847). Our data therefore highlights several genes that warrant further investigation, and of these, TIMP1 shows the greatest potential as an accessible and translational CNP biomarker.

Circulating tissue inhibitor of matrix metalloproteinase-1 is associated with aldosterone-induced diastolic dysfunction.

To test if collagen markers are associated with aldosterone-induced diastolic dysfunction. Although primary aldosteronism is associated with more prominent cardiac remodeling and diastolic dysfunction, the reversibility of diastolic function is unclear. In addition, there is no known biomarker associated with aldosterone-induced diastolic dysfunction. We enrolled 27 patients with aldosterone-producing adenoma (APA) preparing for adrenalectomy, and 27 patients with essential hypertension prospectively from October 2006 to March 2010 at a tertiary referral center. Plasma matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were measured, and echocardiography including tissue Doppler images was performed in both groups and 1 year after receiving adrenalectomy in the APA group. The baseline plasma TIMP-1 level (88.4 ± 38.7 vs. 63.6 ± 32.5 ng/ml; P = 0.014), left ventricular mass index (LVMI), and E/E' ratio (11.5 ± 2.9 vs. 9.0 ± 2.1; P < 0.001) were significantly higher in the APA group. The baseline plasma TIMP-1 level significantly correlated with the E/E' ratio, LVMI, interventricular septum, and left atrial diameter. The plasma MMP-2 level did not correlate with the left ventricular structure parameters, except for interventricular septum thickness. After adrenalectomy, LVMI and E/E' ratio improved significantly. The postadrenalectomy plasma TIMP-1 levels, but not MMP-2 levels, also decreased. The change of plasma TIMP-1 levels was negatively associated with the postadrenalectomy E/E' ratio after adjustment for age, sex, BMI, and mean blood pressure (β-coefficient = - 3.6, P = 0.004). Excess of aldosterone induces cardiac diastolic dysfunction, which is reversible by adrenalectomy. TIMP-1 is associated with the aldosterone-induced diastolic dysfunction.

Plasma matrix metalloproteinase-3 correlates with the clinical severity in men with multiple system atrophy

Aim Matrix metalloproteinase-3 (MMP-3), MMP-9 and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) play roles in remodeling and repairing tissue. The aim of the present study was to investigate correlations between plasma levels of these proteins and clinical severity of multiple system atrophy (MSA). Methods MMP-3, MMP-9 and TIMP-1 levels were measured by enzyme-linked immunosorbent assay (ELISA) in 72 MSA patients and 48 adult controls. Clinical severity was rated with the scale for assessing and rating ataxia (SARA) and the unified MSA rating scale (UMSARS). Immunohistochemistry and immunoblotting were used to assess MMP-3 expression in post-mortem brain tissue. Results Plasma MMP-3 was significantly lower in females than males, but MMP-9 and TIMP-1 showed no sex difference. Compared with age-matched controls (age ≥40 years), male MSA patients had significantly lower plasma MMP-3, but no difference was detected in female MSA patients versus controls. We observed significant correlations with rating scales in male, but not female, patients; plasma TIMP-1 positively correlated with SARA and UMSARS, whereas plasma MMP-3 showed an inverse correlation with the rating scales. These correlations became more evident when the MMP-3/TIMP-1 ratio was used as an index. Plasma MMP-9 did not correlate with any scales in male patients, but was positively correlated with UMSARS in female patients. Immunohistochemical studies of post-mortem brain tissues showed that total cerebellar MMP-3 expression was not significantly different between MSA patients and controls, but glial cytoplasmic inclusions were intensely immunoreactive for MMP-3. Conclusion MMP-3 and TIMP-1 are possible biomarker candidates for MSA. However, it is unclear whether they accurately reflect clinical progression.

Plasma level of tissue inhibitor of matrix metalloproteinase-1 but not that of matrix metalloproteinase-8 predicts survival in head and neck squamous cell cancer

Expression of matrix metalloproteinase-8 (MMP-8) in tongue cancer cells has been associated with an improved prognosis. MMP-8 is inhibited by tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and elevated levels of TIMP-1 in blood have been associated with poor prognosis in many cancers. We wished to evaluate the usefulness of peripheral blood MMP-8 and TIMP-1 levels as well as the genotypes of MMP8 and TIMP1 in predicting prognosis in head and neck squamous cell carcinoma (HNSCC). Plasma concentrations of MMP-8 and TIMP-1 were analyzed in 136 HNSCC patients. MMP8 and TIMP1 genotypes were determined by analysis of single nucleotide polymorphisms (SNP) in peripheral blood DNA. The mean follow-up time was 3.3years. We found that plasma MMP-8 level did not predict survival but that TIMP-1 level was associated with survival. The adjusted hazard ratio of death scored as a continuous variable on the log(10) scale was 23.2 (95% CI 1.88-286, P=0.01) and that of MMP-8 1.24 (95% CI 0.54-2.84, P=0.61). Immunohistochemical staining showed that TIMP-1 was expressed in vascular endothelium of tumor. TIMP-1 levels were associated with TIMP1 genotype in women but not in men. MMP8 genotype did not correlate with survival or MMP-8 level. Plasma TIMP-1 levels predict survival in HNSCC. TIMP-1 expression is genetically controlled in women. As TIMP-1 inhibits the activity of MMP-8 and it also functions as a growth factor, it may directly influence HNSCC progression.

Ventricular remodeling and matrix metalloproteinase-1 and its tissue inhibitor of metalloproteinase-1 in serum in third trimester of pregnant women with cardiac disease.

To analyse the relationship between the left ventricular (LV) structure, function and changes of concentration of serum matrix metalloproteinase-1 (MMP-1), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), and evaluate the value of the change of serum MMP-1 and serum TIMP-1 in ventricular remodeling of pregnant women complicating cardiac disease. Fifty-eight cases of pregnant women with cardiac disease divided into three groups [group A had 17 cases who had clinical manifestations and no left ventricular hypertrophy (LVH)], group B had 15 cases who had clinical manifestations and LVH but no pulmonary hypertension (PH), group C had 26 cases who had clinical manifestations, LVH and PH which divided into three groups again: 11 cases of slight group [PH from 30 - 49 mm Hg (1 mm Hg = 0.133 kPa)], 9 cases of moderate group (PH from 50 - 79 mm Hg) and 6 cases of severe group (PH >/= 80 mm Hg). Fifteen healthy pregnant women acted as control group. The left ventricular structure and function [(left ventricular mass index (LVMI), left ventricular end-diastolic diameter (LVEDd), Ejection fraction (EF), E peak (E), A peak (A) and E/A], pulmonary pressure and plasma MMP-1, TIMP-1 values were determined in the third trimester of pregnancy. (1) LVMI (148 +/- 7) g/m(2) and LVEDd (58.9 +/- 3.5) mm in group C increased significantly (totally P < 0.01), EF (51.0 +/- 4.4)% decreased significantly (P < 0.01), E (50 +/- 10) cm/s decreased significantly (P < 0.01), A (81 +/- 13) cm/s increased (P < 0.05) and E/A (0.6 +/- 0.3) decreased significantly (P < 0.01) compared with normal subjects, group A and group B. (2) LVMI (150 +/- 7) g/m(2), LVEDd (69.7 +/- 3.4) mm in severe pulmonary hypertension group increased significantly (P < 0.01), EF (45.6 +/- 2.6)% decreased significantly (P < 0.01), E (44 +/- 9) cm/s decreased (P < 0.05), A (86 +/- 8) cm/s increased (P < 0.05) and E/A (0.52 +/- 0.17) decreased significantly(P < 0.01) compared with slight and moderate pulmonary hypertension group. (3) Plasma MMP-1 (41 +/- 10) microg/L and TIMP-1 (393 +/- 37) microg/L values in group C increased significantly compared with normal subjects, group A and group B (P < 0.01).(4) Plasma MMP-1 (42 +/- 7) microg/L and TIMP-1 (411 +/- 31) microg/L values of severe pulmonary hypertension group increased significantly compared with slight pulmonary hypertension group (P < 0.05, P < 0.01). (5) The correlation analysis indicated that: There was positive correlation between the serum concentration of MMP-1 and TIMP-1 (r = 0.587, P < 0.01). The serum concentration of MMP-1 was positively correlated with LVMI and LVEDd significantly (r = 0.782, P < 0.001; r = 0.648, P < 0.01) and was negatively correlated with EF significantly (r = -0.587, P < 0.01). (6) Plasma MMP-1 values > 50 microg/L and plasma TIMP-1 values > 450 microg/L in 3 cardiac disease failure cases. (1) The ventricular remodeling can be found in the third trimester of pregnancy of women complicating cardiac disease, and the more serious the left ventricular hypertrophy and PH, the more obvious the ventricular remodeling. (2) The changes in the plasma MMP-1/TIMP-1 values and MMP-1/TIMP-1 balance may play an important role in the left ventricular structural, functional, and clinical manifestations of pregnant women complicating cardiac disease. (3) An increased MMP-1 and TIMP-1 level maybe can predict the presence of cardiac disease failure.

Plasma Tissue Inhibitor of Matrix Metalloproteinase-1 Level Is Increased in Normotensive Non-Dippers in Association with Impaired Glucose Metabolism

Non-dipping (nocturnal blood pressure [BP] decrease<10%) is related to accelerated urinary salt excretion (u-NaCl), and increased risk of left ventricular hypertrophy (LVH) and cardiovascular events. We evaluated whether non-dippers exhibit an advanced extracellular matrix fibrosis, in relation to increased u-NaCl, among normotensive subjects. We measured plasma tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), a marker of collagen fibrosis in extracellular matrix, to evaluate the relationship between non-dipping and u-NaCl in 73 normotensive subjects (no antihypertensive medications, clinic BP<140/90 mmHg and/or 24-h ambulatory BP<125/80 mmHg). Non-dippers had a significantly higher percentage of subjects with impaired fasting glucose (IFG) or diabetes mellitus (DM), and had a greater left ventricular mass index (LVMI), plasma TIMP-1 level and u-NaCl than dippers (IFG or DM: 24.0 vs. 6.3%, p=0.029; LVMI: 118+/-31 vs. 103+/-26 g/m(2), p=0.039; TIMP-1: 168+/-35 vs. 151+/-30 pg/mL, p=0.035; u-NaCl: 5.1+/-1.7 vs. 3.9+/-1.7 g/12 h, p=0.005). In logistic regression analysis, non-dipping was independently associated with u-NaCl and TIMP-1. u-NaCl was correlated with non-dipping (r=0.35, p=0.003) and serum glucose level (r=0.26, p=0.027). On the other hand, TIMP-1 level was significantly correlated with the presence of IFG or DM (r=0.23, p=0.046), but not with u-NaCl. In conclusion, plasma TIMP-1 level, a measure of cardiovascular fibrosis in extracellular matrix, is greater in normotensive non-dippers than in dippers; however, the increased TIMP-1 level may be related to impaired glucose metabolism, and non-dipping may be related to increased u-NaCl associated with high serum glucose levels in normotensive subjects. (Hypertens Res 2008; 31: 2045-2051).

Serological evidence of early remodeling in high-risk non-ST elevation acute coronary syndromes

Introduction Non-ST elevation acute coronary syndrome (ACS) represents a spectrum of risk, with electrocardiographic (ECG) changes and a positive troponin being associated with higher morbidity and mortality. Ischaemia produces alterations in the collagenous component of the heart, even in the absence of myocyte necrosis. Collagen turnover can be assessed biochemically with C-propeptide for type I collagen (PICP) and C-telopeptide for type I collagen (CITP) being markers of collagen synthesis and degradation respectively. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is a marker of inhibition of degradation. Methods Fifty-two patients with non-ST elevation acute ACS were recruited and dichotomised into high- and low-risk groups based on ECG and troponin level. Sequential measurements of plasma PICP, CITP and TIMP-1 were performed over a 48 hour period. Results Twenty were classified as low-risk (negative troponin and normal ECG) and 32 as high-risk. PICP was within the normal range at all time points in both groups. However, admission CITP was higher in the high-risk group (3.7 vs. 2.6 ng/ml, p < 0.001) and, unlike the low-risk group, demonstrated a further rise over 48 h. Similarly, mean TIMP-1 displayed a sequential change over time in the high-risk group only, and admission level was higher compared to the low-risk group (302 vs. 221 ng/ml, p < 0.01). Discussion There is serological evidence of time-dependent altered collagen metabolism in high-risk ACS, which is not present in the low-risk group. This may reflect a degree of remodeling and may aid risk stratification of patients presenting with non-ST elevation ACS.

Involvement of matrix metalloproteinases in the regulation of myocardial extracellular matrix in patients with congestive heart failure

To investigate the expression of the matrix metalloproteinases (MMP)-2, -3, and 9, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), fibronectin (FN), and tenascin-C (TN-C) in the myocardium, and their relationship with the myocardial remodeling and heart function in the patients with congestive heart failure (CHF). A few tissues of papillary muscles of left ventricle were taken from 39 patients with mitral insufficiency during mitral valve replacement, and from 8 organ donors who had died of accidents to undergo pathological examination and to detect the protein expression of MMP-2, -3, and 9, and TIMP-1 by immunoprecipitation and the expression of FN and TN-C by immunofluorescence test. Peripheral blood samples were collected from these 39 patients and 30 normal controls to examine the plasma MMPs and TIMP-1 by ELISA. Typical myocardial remodeling was seen in the myocardial tissues of the CHF patients. The plasma levels of MMP-2, -3, and -9 of the CHF patients in the cardiac function classes II - IV were all significantly higher than those of the normal controls (P < 0.05 or P < 0.01) with a tendency to increase with the deterioration of heart function, The plasma level of TIMP-1 of the CHF patients in the cardiac function classes II - IV were all significantly higher than that of the normal controls (P < 0.05 or P < 0.01) with a tendency to decrease with the deterioration of heart function. The protein expression levels of MMP-2, -3, and -9 in the myocardium of the CHF patients in the cardiac function classes III - IV were all significantly higher than those of the normal controls (P < 0.05 or P < 0.01) with a tendency to increase with the deterioration of heart function. The protein expression levels of TIMP-1 in the myocardium of the CHF patients in the cardiac function classes III - IV were all significantly lower than that of the normal controls (P < 0.05 or P < 0.01) with a tendency to decrease with the deterioration of heart function. The protein expression levels of FN in the myocardium of the CHF patients in the cardiac function classes II - IV were all significantly lower than that of the normal controls (all P < 0.05) with a tendency to decrease with the deterioration of heart function. The protein expression levels of TN-C in the myocardium of the CHF patients in the cardiac function classes II - IV were all significantly higher than that of the normal controls (all P < 0.01) with a tendency to increase with the deterioration of heart function. The increasing expression of MMP-2, -3, and -9 and the decreasing expression of TIMP-1 contribute to the myocardial remodeling, thus changing the extracellular matrix in the myocardium tissue and leading to the development and progression of CHF.

Prognostic value of tissue inhibitor of matrix metalloproteinase-1 in plasma of patients with gastric cancer

Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in plasma has been reported to be related to disease progression in patients with gastric cancer. However, the prognostic significance of plasma TIMP-1 concentrations has not been clarified. Concentrations of TIMP-1 protein were measured by enzyme-linked immuno-sorbent assay in plasma samples of 147 preoperative patients who subsequently underwent gastric resection, and prognosis was compared. The cut-off value of plasma TIMP-1 concentrations was defined as 112.5 ng/ml, referring to the TIMP-1 levels in patients with intramucosal gastric cancer. Twenty-nine out of 147 patients had higher plasma TIMP-1 levels than the cut off value. When the patients were divided into those with elevated values and those with normal TIMP-1, such parameters as age, serosal invasion, metastases to lymph nodes, peritoneum, and liver, lymphatic invasion, curability, and stage were significantly different between the two. By univariate analysis of the factors affecting survival, macroscopic type, histology, serosal invasion, metastasis to lymph node, peritoneum, and liver, vessel invasions, curability, and plasma TIMP-1 were significant. However, multivariate analysis revealed that TIMP-1 was the only significant factor. In patients with gastric cancer, plasma TIMP-1 seem to be an independent and most powerful prognosticator for the survival.

Tissue inhibitor of matrix metalloproteinase-1 in the plasma of patients with gastric carcinoma. A possible marker for serosal invasion and metastasis.

Expression of the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in tumor tissue from patients with gastric carcinoma has been reported to be related to disease progression. However, to the authors' knowledge the clinical significance of plasma TIMP-1 concentrations in these patients has not been clarified. Concentrations of TIMP-1 protein were examined by enzyme-linked immunoadsorbent assay in plasma samples from 149 patients who underwent resection of their primary tumors and from 18 patients with nonresected or recurrent disease. In the 149 patients whose primary tumors were resected, plasma TIMP-1 concentration was associated significantly with a variety of pathologic factors including macroscopic type, depth of invasion, lymph node and peritoneal metastases, vessel invasion, pattern of tumor infiltration into surround ing tissue, and disease stage. Plasma TIMP-1 concentration was significantly higher in patients with serosal invasion, lymph node metastasis, peritoneal dissemination, or liver metastasis than in those without these factors. Neither carcinoembryonic antigen (CEA) nor CA 19-9 concentrations appeared to be related to these measures of disease progression. In the 18 patients with nonresected or recurrent disease, TIMP-1, CEA, and CA 19-9 were similarly sensitive in predicting peritoneal, liver, and lymph node metastases. The combination of these three factors was able to detect 73.3% of patients with peritoneal metastasis, 83.3% of patients with liver metastasis, and 88.9% of patients with disease recurrence. In patients with gastric carcinoma, plasma concentration of TIMP-1 appears to correlate with both serosal invasion and metastasis.