Circulating Matrix Metalloproteinases Research Articles

Circulating matrix metalloproteinase 9 levels in relation to sampling methods, femoral and carotid atherosclerosis

To examine whether circulating levels of matrix metalloproteinase 9 (MMP-9) were associated with ultrasound-assessed intima-media thickness (IMT) and echolucent plaques in the carotid and femoral arteries. To examine preanalytical sources of variability in MMP-9 concentrations related to sampling procedures. Plasma and serum MMP-9 levels were compared with ultrasound assessed measures of femoral and carotid atherosclerosis, in a cross-sectional study of 61-year-old men (n = 473). Preanalytical sources of variability in MMP-9 levels were examined in 10 healthy subjects. Main outcome measures were circulating levels of MMP-9 in serum and plasma, IMT of the carotid and femoral arteries, and plaque status based on size and echolucency. Research unit at university hospital. Plasma concentrations of total and active MMP-9 were associated with femoral artery IMT independently of traditional cardiovascular risk factors, and were higher in subjects with moderate to large femoral plaques. Plasma MMP-9 concentration was higher in men with echolucent femoral plaques (P = 0.006) compared with subjects without femoral plaques. No similar associations were found for carotid plaques. MMP-9 concentrations were higher in serum than in plasma, and higher when sampling was performed with Vacutainer than with syringe. MMP-9 levels in serum were more strongly associated with peripheral neutrophil count compared with MMP-9 levels in plasma. Plasma MMP-9 levels were associated with atherosclerosis in the femoral artery, and total MMP-9 concentration was higher in men with echolucent femoral plaques. The choice of sample material and sampling method affect the measurements of circulating MMP-9 levels.

Reductions of Circulating Matrix Metalloproteinase 2 and Vascular Endothelial Growth Factor Levels after Treatment with Pegvisomant in Subjects with Acromegaly

Vascular endothelial growth factor (VEGF) is involved in activation of the matrix metalloproteinase (MMP) system; the latter is implicated in atherosclerosis and cardiovascular disease. Patients with acromegaly have reduced life expectancy primarily due to cardiac disease. This study assessed plasma MMPs and VEGF levels in patients with active acromegaly (IGF-I > 130% upper limit of normal), and on treatment with pegvisomant. Twenty patients [nine female, mean age 56.1 +/- 13.8 yr (mean +/- sd)] were studied at baseline and on pegvisomant therapy and compared with data from 25 healthy volunteers (12 female; 56.6 +/- 14.2 yr). Plasma MMP-2, MMP-9, and VEGF levels were measured. Serum IGF-I fell from a baseline (mean +/- sd) level of 620.1 +/- 209.3 ng/ml to 237.5 +/- 118.5 ng/ml on pegvisomant (doses 10-60 mg; P < 0.001). MMP-2 levels at baseline were significantly higher in patients compared with healthy controls (380.7 +/- 204.8 vs. 207.4 +/- 62.6 ng/ml; P < 0.001), but with treatment a significant reduction in MMP-2 [380.7 +/- 204.8 vs. 203.0 +/- 77.4 ng/ml; P < 0.001] and VEGF (283.4 +/- 233.6 vs. 229.1 +/- 157.4 pg/ml; P = 0.008) was noted. There was no significant difference in MMP-9 levels between patients and controls at baseline (797.5 +/- 142.1 vs. 788.3 +/- 218.0 ng/ml; P = 0.87) or between baseline and posttreatment levels (797.5 +/- 142.1 vs. 780.0 +/- 214 ng/ml; P = 0.76). Our novel data demonstrate that treatment of acromegaly with pegvisomant leads to reductions in MMP-2 and VEGF concentrations. Further studies are required to determine the significance of these findings with relation to cardiac disease.

Sample processing and its preanalytical impact on the measurement of circulating matrix metalloproteinases

Sample processing and its preanalytical impact on the measurement of circulating matrix metalloproteinases

Comparison of Levels of Matrix Metalloproteinase-2 and -3 in Patients With Ischemic Cardiomyopathy Versus Nonischemic Cardiomyopathy

It has been reported that circulating matrix metalloproteinase (MMP) levels are upregulated in patients with chronic heart failure. However, experimental studies indicate that differences in the profiles of MMPs and tissue inhibitors of metalloproteinase (TIMPs) may exist in ischemic compared with nonischemic cardiomyopathy. This study examined whether circulating levels of MMPs and TIMP-1 are related to the pathogenesis of heart failure. Circulating levels of MMP-2, MMP-3, and TIMP-1 were assessed in 52 patients with compensated end-stage chronic heart failure, including 26 patients (mean 64 +/- 7 years; 10 men) with ischemic cardiomyopathy (IC) and 26 (mean age 66 +/- 6 years; 14 men) with idiopathic dilated cardiomyopathy (IDC). Serum MMP-2 (p <0.001) and MMP-3 (p <0.001) levels were higher in patients with IDC than in those with IC. Serum TIMP-1 levels were lower in patients with IDC (p = 0.011) than in those with IC. This study shows that in patients with compensated end-stage chronic heart failure, circulating levels of MMP-2, MMP-3, and TIMP-1 are associated with the pathogenesis of heart failure.

Alteplase treatment affects circulating matrix metalloproteinase concentrations in patients with ST segment elevation acute myocardial infarction

Introduction Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques. Acute coronary syndromes may be precipitated by MMPs through degradation of the fibrous cap and subsequent plaque disruption. Serine proteases such as plasmin activate MMPs and may contribute to plaque events. Thrombolysis with recombinant tissue plasminogen activator (rtPA) is widely used for treatment of acute ST segment elevation myocardial infarction (STEMI). In the present study we assessed whether thrombolytic therapy with rtPA in patients with STEMI influences serum levels of MMP-2 and MMP-9. Methods We recruited 108 patients (92 men, mean age 64 ± 12 years) with STEMI, of whom 84 (78%) received thrombolytic treatment with rtPA and 24 (22%) did not. MMP-2 and MMP-9 levels were assessed at hospital admission (baseline), and at 24 and 72 h after admission, using a commercially available ELISA. Results Overall, MMP-9 levels were higher in the thrombolysis group compared to patients without thrombolysis ( p < 0.001). Thrombolysis treatment significantly affected the change in MMP-9 levels during the 72-h study period ( p < 0.001). Conclusions The present study showed that thrombolysis could affect circulating levels of MMP-9 in STEMI patients. Whether this effect may lead to plaque instability deserves further investigation.

Gelatinases and their tissue inhibitors in ovarian tumors; TIMP-1 is a predictive as well as a prognostic factor

Objective. In the present study, the significance of circulating matrix metalloproteinases -2 and -9 (MMP-2, MMP-9), as well as their tissue inhibitors -1 and -2 (TIMP-1, TIMP-2) in ovarian cancer were studied to assess the possibility of using them in clinical decision-making. Methods. We measured, prior to primary surgery, the concentrations of these proteins in serum samples of 115 patients with an ovarian tumor: 63 with cancer, 6 with a low malignant potential tumor, and 46 with a benign tumor. The measurements were performed with enzyme-linked immunosorbent assays (ELISA). The results were compared to clinicopathological data. Results. A high serum concentration of TIMP-1 at diagnosis was found to correlate with the malignant phenotype of an ovarian tumor. Within malignant neoplasias, high circulating TIMP-1 correlated to the aggressive phenotype and unfavorable prognosis. An association was found between a high serum level of TIMP-1 and an advanced stage of the disease, a residual tumor >2 cm, poor response to cytotoxic treatment, shorter recurrence free time, and shorter cancer-related overall survival. No statistically significant correlation was found between the circulating gelatinases (MMP-2, MMP-9) or TIMP-2 and the clinicopathological factors. However, a tendency for better survival with high serum concentration of TIMP-2 or MMP-2 was observed. Conclusion. We conclude that an elevated preoperative serum TIMP-1 concentration correlates to the aggressive behavior of ovarian cancer.

Consideration of Preanalytical Conditions to Use Circulating Matrix Metalloproteinases as Diagnostic Markers

Consideration of Preanalytical Conditions to Use Circulating Matrix Metalloproteinases as Diagnostic Markers

Preanalytical Conditions and Circulating Matrix Metalloproteinases

Preanalytical Conditions and Circulating Matrix Metalloproteinases

Effect of Treatment With Candesartan or Enalapril on Subcutaneous Small Artery Structure in Hypertensive Patients With Noninsulin-Dependent Diabetes Mellitus

Structural alterations of subcutaneous small resistance arteries are associated with a worse clinical prognosis in hypertension and noninsulin-dependent diabetes mellitus (NIDDM). However, no data are presently available about the effects of antihypertensive therapy on vascular structure in hypertensive patients with NIDDM. Therefore, we have investigated the effect of an angiotensin-converting enzyme inhibitor, enalapril, and a highly selective angiotensin receptor blocker, candesartan cilexetil, on indices of subcutaneous small resistance artery structure in 15 patients with mild hypertension and NIDDM. Eight patients were treated with candesartan (8 to 16 mg per day) and 7 with enalapril (10 to 20 mg per day) for 1 year. Each patient underwent a biopsy of the subcutaneous fat from the gluteal region at baseline and after 1 year of treatment. Small arteries were dissected and mounted on a micromyograph and the media-to-internal lumen ratio was evaluated; moreover, endothelium-dependent vasodilation to acetylcholine was assessed. A similar blood pressure-lowering effect and a similar reduction of the media-to-lumen ratio of small arteries was observed with the 2 drugs. Vascular collagen content was reduced and metalloproteinase-9 was increased by candesartan, but not by enalapril. Changes of circulating indices of collagen turnover and circulating matrix metalloproteinase paralleled those of vascular collagen. The 2 drugs equally improved endothelial function. In conclusion, antihypertensive treatment with drugs that inhibit the renin-angiotensin-aldosterone system activity is able to correct, at least in part, alterations in small resistance artery structure in hypertensive patients with NIDDM. Candesartan may be more effective than enalapril in reducing collagen content in the vasculature.

Careful attention to blood sampling as a preanalytical determinant of circulating matrix metalloproteinase 9 to avoid misinterpretations: Comment on the article by Ainiala et al

Careful attention to blood sampling as a preanalytical determinant of circulating matrix metalloproteinase 9 to avoid misinterpretations: Comment on the article by Ainiala et al

Temporal association between circulating proteolytic, inflammatory and neurohormonal markers in patients with coronary ectasia

Background: The prevalence of coronary ectasia (CE) appears to rise in recent years. However, the pathogenetic mechanisms that underlie this entity are not understood. We hypothesized that dysregulation of circulating matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) contributes to ectasia formation. We also evaluated the association of MMP with inflammatory or the neurohormonal markers. Methods: We screened coronary angiographic procedures conducted in our hospital. Thirty-four patients with CEs were identified; 17 with a single ectasia and 17 with generalized ectasias. Two control groups; patients with atherosclerotic coronary disease ( n = 26) and patients with normal coronary arteries ( n = 27) were chosen randomly. Serum levels of MMP-2, MMP-3 and TIMP-1 were determined by ELISA. Pro B-type natriuretic peptide (proBNP) and high sensitivity C-reactive protein (hsCRP) serum levels were also measured. Results: Serum levels of MMP-2, MMP-3, TIMP-1, proBNP and hsCRP did not differ between the three groups of patients. However, subgroup analysis demonstrated that MMP-3 level is significantly lower in patients with generalized CEs compared to those with single vessel ectasia. We also found a statistically significant correlation between proBNP and MMP-2/TIMP-1 (for MMP-2: r 2 = 0.3, p = 0.003 and for TIMP-1 r 2 = 0.42, p < 0.000l). By performing subgroup analysis we found that this correlation is only demonstrated in patients with CEs. No correlation was demonstrated between hsCRP and MMPs/TIMP. Conclusions: These observations suggest that MMP/TIMP imbalance is present in patients with generalized CE and may contribute to ectasia formation. This imbalance could be mediated by BNP.

W01.86 Circulating matrix metalloproteinases are altered in patients with hypercholesterolemia: The effect of atorvastatin treatment

W01.86 Circulating matrix metalloproteinases are altered in patients with hypercholesterolemia: The effect of atorvastatin treatment

W01.86 Circulating matrix metalloproteinases are altered in patients with hypercholesterolemia: The effect of atorvastatin treatment

W01.86 Circulating matrix metalloproteinases are altered in patients with hypercholesterolemia: The effect of atorvastatin treatment

Circulating matrix metalloproteinase‐2 is elevated in patients with congestive heart failure

It has been reported that matrix metalloproteinase (MMP) protein concentration and activity are upregulated in the failing human heart. However, there are few reports describing the role of elevated level of circulating MMPs in congestive heart failure (CHF) patients. This study examined whether circulating matrix metalloproteinases (MMPs) are also related to the pathogenesis of CHF. We measured circulating levels of matrix metalloproteinase-2 (MMP-2) in 52 patients with CHF (left ventricular ejection fraction (LVEF) <50%). The patients were also subdivided into two groups according to NYHA functional class; mild CHF (class II, n=43) and severe CHF (class III, n=9). The serum level of MMP-2 and MMP-2/TIMP-2 ratio were significantly higher in CHF than in controls (P<0.01). Among patient groups, serum levels of MMP-2 were significantly higher in patients with severe CHF than in patients with mild CHF (P<0.01). Plasma levels of BNP had a significant positive correlation with circulating levels of MMP-2 (r=0.78; P<0.01) and MMP-2/TIMP-2 ratio (r=0.60; P<0.01). Our data showed that the circulating MMP-2 concentration was increased in CHF patients and that the levels were related to the plasma levels of BNP in CHF, suggesting that the elevated levels are related to developing heart failure syndrome.

Determination of the serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in patients with either advanced small-cell lung cancer or non-small-cell lung cancer prior to treatment

This study was undertaken to examine the relationship between circulating matrix metalloproteinase (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in our patients with either advanced small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC) prior to treatment. Thirty-one male and female patients with either stage III or IV NSCLC and 17 with either stage III or IV SCLC were compared to 117 age matched non-smoking controls of both sexes. Prior to any treatment of the patient, a baseline serum sample was obtained from each of the patients for the determination of circulating MMP-9 and TIMP-1 by ELISA. The results indicate that both MMP-9 and TIMP-1 are elevated in the serum of lung cancer patients when compared to the controls. This observation was true for both SCLC and NSCLC. However, the mean values for both MMP-9 and TIMP-1 in the two tumors were not different from each other. The natural physiological relationship between MMP-9 and the inhibitor TIMP-1 was lost in both SCLC and NSCLC, indicative of abnormal alterations by the tumor. The data from this study suggests that advanced lung cancer does alter the normal circulatory pattern of MMP-9 and TIMP-1. This could aid in the processes of tumor invasion and/or metastasis.

Response

Response

Long-term treatment with pitavastatin (NK-104), a new HMG-CoA reductase inhibitor, of patients with heterozygous familial hypercholesterolemia

The clinical efficacy and safety of pitavastatin (NK-104), a novel HMG-CoA reductase inhibitor, during long-term treatment, were examined in 25 patients (male/female=11/14, mean age=53±13 (mean±SD) years) with heterozygous familial hypercholesterolemia (FH). After a period on placebo of >4 weeks, 2 mg/day of pitavastatin was administered for 8 weeks, and the dose was increased to 4 mg/day for up to 104 weeks. Total cholesterol (TC) decreased by 31% from the initial value of 340±57 to 237±40 mg/dl ( P<0.0001) at week 8. During treatment with the higher dose, TC decreased even further to 212±35 mg/dl at week 12; it decreased by 37% from the initial value ( P<0.0001). Similarly, the baseline low-density lipoprotein (LDL)-cholesterol (LDL-C) decreased by 41% at week 8, and by 49% at week 12, from 267±61 mg/dl at baseline. These findings indicate a dose-dependent effect of the drug on TC and LDL-C concentrations. To examine whether the levels of circulating matrix metalloproteinases (MMPs) and their endogenous inhibitors (tissue inhibitors of metalloproteinases: TIMPs) are altered during lipid-lowering therapy, we also measured their plasma levels. The mean levels of MMP-2 and -3 were significantly increased. No significant alteration was found in MMP-9, TIMP-1 and -2 levels. As for the safety of pitavastatin, adverse reactions were observed in one case (4%) of subjective and objective symptoms. The effects of pitavastatin on TC and LDL-C were stable during long treatment of patients with heterozygous FH.

Circulating matrix metalloproteinase may relate to proinflammatory cytokine in patients with dilated cardiomyopathy Taketoshi Yamazaki, Jong-Dae Lee, Hiromasa Shimizu, Hiroyasu Uzui, Yasuhiko Mitsuke, Takanori Ueda. Fukui Medical University, Fukui, Japan

Circulating matrix metalloproteinase may relate to proinflammatory cytokine in patients with dilated cardiomyopathy Taketoshi Yamazaki, Jong-Dae Lee, Hiromasa Shimizu, Hiroyasu Uzui, Yasuhiko Mitsuke, Takanori Ueda. Fukui Medical University, Fukui, Japan

Expression of Matrix Metalloproteinase-2 and -9 and Their Inhibitors in Peripheral Blood Cells of Patients with Chronic Hepatitis C

To clarify whether circulating matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) can be used as serum markers of fibroproliferation in chronic liver diseases, we studied the expression of MMP-2 and MMP-9 in relation to TIMP-1 and TIMP-2 in peripheral blood mononuclear leukocytes (MNLs) and polymorphonuclear leukocytes (PMLs), and compared this expression to circulating concentrations and hepatic histology in patients with chronic active hepatitis C (CAH). Quantitative reverse transcription-PCR/ELISA assays were performed for MMP and TIMP RNA, and corresponding circulating protein concentrations were studied by ELISA in 20 healthy controls, 40 patients with CAH, and 20 patients with hepatitis C-induced cirrhosis (Ci). MMP-2 mRNA was found almost exclusively in the liver, MMP-9 mRNA in leukocytes. TIMP RNA-equivalents were decreased in MNLs of CAH patients, but neither MMP-9 nor TIMP RNA expression showed any correlation to the extent of inflammation and fibrosis. MMP-2 and TIMP-1 protein concentrations were increased in Ci patients and showed a wide overlap in CAH patients and healthy controls. MMP-9 values were lower in CAH and Ci patients than in healthy controls. TIMP-2 values showed a wide overlap in all three groups. The MMP-2/TIMP-1 and MMP-9/TIMP-1 ratios were lower in Ci patients than in healthy controls; the MMP-2/TIMP-2 and MMP-9/TIMP-2 ratios were not different. Circulating TIMP-1 and the MMP-2/TIMP-1 ratio correlated to the inflammatory activity in liver biopsies, but only the circulating MMP-2/TIMP-1 ratio also correlated with the degree of fibrosis. Peripheral blood cell expression of MMP-2, MMP-9, and TIMP revealed no correlation with the circulating concentrations of these proteins. Only the circulating MMP-2/TIMP-1 ratio correlated to the histological degree of fibrosis in hepatitis C and should be further evaluated as a progression marker in patients with chronic liver disease.

Anti-tumour necrosis factor specific antibody (infliximab) treatment provides insights into the pathophysiology of rheumatoid arthritis

Preclinical studies based on in vitro cell systems and in vivo models had established a position for tumour necrosis factor (TNF) α as a pivotal molecule regulating cellular activation and...