Matrix metalloproteinase 3 and 9 as genetic biomarkers for the occurrence of cardiovascular complications in coronary artery disease: a prospective cohort study.

BACKGROUND: Matrix metalloproteinases (MMPs) are widely expressed in atherosclerosis lesions. The disequilibrium of MMPs driving to an overexpression or a lack of its level can be influenced by genetic variations. MMP-3 and MMP-9 may be affected by specific polymorphisms like - 1612 5 A/6A and the - 1562 C/T respectively. We aim in the present study to investigate prospectively the association between the - 1612 5 A/6A MMP-3 and - 1562 C/T MMP-9 polymorphisms and clinical outcomes in patients with coronary artery disease (CAD). This study is elaborated to reveal whether one of these polymorphisms is a probable predictor of cardiovascular complications in this CAD cohort. METHODS AND RESULTS: A total of 168 patients with CAD were prospectively followed up over a period of 5 years. Genotypes for the MMP-3 (-1612 5 A/6A) and MMP-9 (-1562 C/T) polymorphisms were performed using PCR-RFLP. Their levels were measured by ELISA in Sandwich test during the follow-up period, 39 cardiovascular outcomes occurred with 21 repeat targets for revascularization, 3 patients with Myocardial infarction, 8 for heart failure, 5 for Stroke and 2 for cardiovascular mortality. The MMP-3 5 A/6A polymorphism was related to the disease on the contrary of the MMP-9 -1562 C/T. Patients carrying the 5 A allele had a higher level of MMP-3 level and those who carried the 6 A allele had lower level (p = 0.04). After applied multivariable Cox-hazard models we revealed that the 6 A allele is independently associated to the disease complication. Kaplan-Meier survival test revealed that individuals having the 6 A allele had a lower survival rate than those with the 5 A allele (p = 0.04). CONCLUSION: Our study suggests the disruption of the MMP-3 level may be due to the existence of the polymorphism - 1612 residing in its promoter region. MMP-3 can be considered as a marker of diagnosis and prediction in cardiovascular events.

Matrix metalloproteinase-7 could be a predictor for acute inflammation in psoriatic patients.

PURPOSE: The pathogenesis of psoriasis is characterized by a disruption of extracellular matrix (ECM) in which matrix metalloproteinases (MMPs) participate actively. We aimed to determine MMP-7 level and its association with the inflammatory response in order to determine its usefulness as a biomarker for psoriasis prediction. We also aimed to determine its distribution in uninvolved and involved psoriatic skin to evaluate the probable role of MMP-7 in psoriasis pathogenesis. MATERIALS AND METHODS: We recruited 108 psoriatic patients and 133 healthy controls. MMP-7, tissue inhibitors of metalloproteinases (TIMPs) and interleukin-6 (IL-6) levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA) assay. MMP-7 expression was detected by Immunohistochemistry (IHC) study. RESULTS: ECM turnover and inflammatory biomarker levels were significantly higher in psoriatic patients. MMP-7 revealed to be independently associated to psoriasis even after adjustment for different models. The area under the curve (AUC) of MMP-7 and inflammation Z-score were similar. MMP-7 was positively correlated with IL-6 and inflammation Z-score. Psoriasis severity (PASI) was correlated significantly with IL-6 (p = 0.007). The MMP-7 expression was detected in the epidermis of involved and uninvolved psoriatic skin. In involved skin, MMP-7 was expressed by basal and mostly suprabasal keratinocytes. In uninvolved skin, expression of MMP-7 was restricted to basal keratinocytes. CONCLUSION: MMP-7 is independently associated to psoriasis disease and to inflammatory response which make it a potential biomarker for this dermatosis.

Matrix metalloproteinase-3 predicts clinical cardiovascular outcomes in patients with coronary artery disease: a 5 years cohort study.

Matrix metalloproteinases (MMPs) are implicated in atherosclerosis evolution into a coronary artery disease (CAD). They could be used as biomarkers for a predictive approach when they are studied simultaneously. We aim in our study to demonstrate prospectively in patients with history of CAD that MMPs level is linked to clinical cardiovascular outcomes. Two hundred and eighteen patients diagnosed with CAD were followed prospectively for 5 years in the Cardiology Department of la Rabta Hospital University. Clinical cardiovascular outcomes during the period of the cohort were recorded. Measures were performed for biological and matrix markers at baseline. MMP-3, MMP-8, MMP-9, TIMP-1 and TIMP-2 were measured by ELISA in Sandwich assay. Fifty-nine cardiovascular outcomes occurred during the cohort period. By multivariate analysis, only MMP-3 persisted as a predictor for cardiovascular events even after adjustment. This metalloproteinase have been shown to be an independent predictor for cardiovascular outcomes (HR = 3.01; CI (1.3-6.95). The found cut-off value by receiver operating curve (ROC) was used for Kaplan-Meier analysis and revealed that patients with MMP-3 level higher than 9.3 ng/mL had a lower survival rate (p = 0.03). MMP-3 baseline level in patients with history of CAD is a potential predictor for cardiovascular outcomes.

Does the dysregulation of matrix metalloproteinases contribute to recurrent implantation failure?

INTRODUCTION: The progress in in vitro fertilization (IVF) techniques for infertility management has led to the investigation of embryo implantation site proteins such as Matrix metalloproteinases (MMPs), which may have a key role in embryo-endometrium crosstalk and in the molecular mechanisms of the embryo implantation. Areas covered: Numerous studies have generated much information concerning the relation between the different proteins at the site of implantation such as cytokines, growth factors, adhesion molecules and MMPs. However, the exact role of the MMPs in embryo implantation and the impact of their dysregulation in recurrent implantation failure have yet to be characterized. Expert commentary: The proteomic investigation of the MMPs and their molecular pathways may enable scientists and clinicians to correct this dysregulation (via appropriate means of prevention and treatment), better manage embryo transfer during IVF cycles, and thus increase the ongoing pregnancy rate.

Inflammations mediators and circulating levels of matrix metalloproteinases: Biomarkers of diabetes in Tunisians metabolic syndrome patients.

AIMS: This study investigates the relationships between matrix metalloproteinases, inflammations mediators and type 2 diabetes mellitus in Tunisians metabolic syndrome (Mets) patients. METHODS: The study has included 239 MetS patients and 247 controls. Mets was defined according to the NCEP-ATPIII report. Mets patients were also divided into two categories: 29 MetS non-diabetics and 210 MetS diabetics. Dysglycemia markers, matrix metalloproteinase-9 (MMP-9), Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), tumor necrosis factor α (TNF-α), C-reactive protein (CRP) levels and White Blood Cells (WBC) counts were determined in patients and controls. RESULTS: In our study, the level of inflammatory markers WBC, TNF-α and matrix metalloproteinases (MMP-8 and MMP-9) were significantly higher in diabetic patients with MetS, as compared with non-diabetic MetS patients. Inflammation mediators and MMP-9 were significantly associated with many clinical characteristics of MetS. The use of ROC "Receiver Operating Characteristic" analysis revealed the impact of TNF alpha on diabetes patients with MetS. In fact TNF alpha was found as a sensitive parameter in these patients with a sensitivity of 85%. CONCLUSION: Inflammation, matrix metalloproteinases and dysglycemia markers are not expressed in isolation but rather concurrently and are continuously interacting with each other, in MetS and diabetics patients. These markers fit with an early stage of cardiovascular disease (CVD); and measuring them could improve the risk evaluation, an early diagnosis, and the prognosis of CVD.

Abnormal Circulating Levels of Metalloproteinase and Their Inhibitor in Hypertensive Patients.

BACKGROUND: The aim of this study was to determine the plasmatic levels matrix metalloproteinases (MMPs): MMP-2, MMP-3, MMP-9, and their inhibitors (TIMPs): TIMP-1 and TIMP-2 in hypertensive patients and healthy subjects. METHODS: The study involved 60 hypertensive patients and 61 adult healthy controls. Pro-MMP-9 and pro-MMP-2 activity was determined by the gelatin zymography method and MMP-3, TIMP-1, and TIMP-2 levels were determined by ELISA method. RESULTS: The mean plasma activity of pro-MMP-9 in the hypertensive group and the control group were significantly different (153.33 ± 129.33 vs. 90.38 ± 97.49 x 10(3) densitometric units/µL; p < 0.01). MMP-3 plasmatic level was significantly higher in hypertensive subjects than healthy subjects (20.24 ± 8.63 vs. 16.41 ± 6.8 ng/mL; p < 0.05), whereas the plasma concentration of TIMP-1 in the hypertensive group was lower than the control group 88.96 ± 26.9 vs. 93.96 ± 27.28 ng/mL. The MMP-3/ TIMP-1 and the MMP-3/TMP-2 ratios were higher in hypertensive subjects than healthy subjects. Also, we have found a significant positive correlation between systolic blood pressure and pro-MMP-9 (r = 0.311, p < 0.001). CONCLUSIONS: The present study identified the existence of abnormalities in plasma markers for extracellular matrix metabolism in hypertensive patients.

Metabolic Syndrome, Independent Predictor for Coronary Artery Disease.

BACKGROUND: Metabolic syndrome (MS) was reported to be associated with coronary artery disease (CAD). The aim of the present study was to assess the association between MS and CAD angiographic severity and to search the predictive value of MS and its individual components for CAD. METHODS: 428 patients who underwent elective coronary angiography at the Cardiology Department were included in the study. MS was defined according to National Cholesterol Education Program (NCEP) Adult Treatment Panel III criteria. CAD severity was determined by Gensini scors. RESULTS: The proportion of CAD (+) who had MS was significantly higher compared to CAD (-) (63.6% vs. 48.6%, p = 0.020). Gensini score and number of MS components were positively correlated (r = 0.144, p = 0.019). The adjusted predictive abilities for angiographic CAD of MS and its individual components showed that high FBG and high TG are predictive factors for CAD in binary logistic regression analysis (OR = 2.238, 95% CI 1.111 - 4.508, p = 0.024 vs. OR = 2.200, 95% CI 1.078 - 4.492, p = 0.030). The OR for CAD risk of different phenotypes in high FBG and/or HTG shows that this combination increased the OR significantly to 2.307. Among the quartets, the cluster with high BP and low HDL-C was the highest risk (OR = 4.879). However, the combination including all components of MS was a significant contributor to CAD risk. CONCLUSIONS: The MS score correlates with the angiographic severity of CAD. The predictive ability for CAD was stronger with high FBG and high TG and associated low HDL-C and high BP, which seem to act synergistically as risk factors for CAD. Therefore, to prevent or decrease this risk of CAD, clinicians should screen for individual abnormalities of MS, mainly elevated blood glucose level and TG.

The measurement of circulating matrix metalloproteinase-8 and its tissue inhibitor and their association with inflammatory mediators in patients with acute coronary syndrome.

BACKGROUND: The aim of the present study was to investigate differences of matrix metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients admitted with acute coronary syndrome (ACS) and its correlation with the widely accepted markers of inflammatory activity, C-reactive protein, fibrinogen, and white blood cell number. METHODS: 315 patients with ACS (165 unstable angina pectoris/non-ST-elevation myocardial infarction, 150 ST elevation myocardial infarction), 111 stable angina (SA) patients, and 296 control subjects were enrolled in the study. All biochemical analyses were carried out using a Hitachi 912 analyzer (Roche). Matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined in citrate plasma by ELISA methods. White blood cells (WBC) and fibrinogen were also determined. RESULTS: The plasma concentrations of matrix metalloproteinase-8, tissue inhibitor of metalloproteinase-1, C-reactive protein, fibrinogen, and WBCs in patients with acute coronary syndrome were significantly higher than those in the control group (p < 0.001). Strong positive associations were observed between MMP-8 and TIMP-1 (r = 0.328, p < 0.001), MMP-8 and CRP (r = 0.171, p < 0.001), MMP-8 and Fibrinogen (r = 0.267, p < 0.001), MMP-8 and WBC (r = 0.163, p < 0.01), TIMP-1 and CRP (r = 0.219, p < 0.01), TIMP-1 and fibrinogen (r = 0.226, p < 0.01), TIMP-1 and WBC (r = 0.094, p < 0.1). Other positive correlations were observed between CRP and fibrinogen, CRP and WBC and fibrinogen and WBC in the patients with ACS. CONCLUSIONS: Observations suggest that ACS show an increase in both remodeling and inflammation markers. In addition, the strong relationship with MMP-8 and inflammatory mediators such as CRP, fibrinogen and WBC in ACS patients suggests that MMP-8 might be an additional marker and/or consequence of inflammatory components in ACS.

Serum lipid level in Tunisian patients with psoriasis.

BACKGROUND: Psoriasis is a common chronic inflammatory skin disorder that has been associated with oxidative stress, abnormal plasma lipid metabolism, and high frequency of cardiovascular events. The aim of this study was to determine lipid profile variations in Tunisian psoriatic patients. METHODS: This study was designed and conducted as a case-control assay with 91 psoriatic patients and 91 controls. The lipid profiles, including serum level of triglycerides, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL), were assessed in both groups. RESULTS: The two groups consisted of 91 patients and 91 controls, each with 45 males and 46 females. In the psoriatic group, serum triglycerides, low density lipoprotein, and very low density lipoprotein cholesterol were significantly higher than in the control group (p < 0.05), while the high density lipoprotein cholesterol (HDL-cholesterol) was significantly decreased in patients with psoriasis compared to controls (p < 0.001). There were no significant differences concerning insulin or insulin resistance and total cholesterol between the two groups. The insulin secretion was significantly higher in patients with psoriasis than in the control group (p = 0.003). However, there was no significant correlation between severity of psoriasis and serum lipid and insulin secretion. A negative correlation (r = -0.253, p = 0.019) was found between PASI index and HDL-C. CONCLUSIONS: A high serum lipid level is significantly more common in psoriatic patients. This could be responsible for higher prevalence of cardiovascular incidents in psoriatic patients. It may be useful to do early screening and treatment of hyperlipidaemia in psoriatic patients to prevent atherosclerosis and its complications.

Peripheral blood levels of matrix and inflammatory mediators are elevated in Tunisian patients with acute coronary syndromes.

BACKGROUND: The aim of the present study was to investigate differences of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients admitted with acute coronary syndrome (ACS), in correlation with the widely accepted markers of inflammatory activity, C-reactive protein, fibrinogen, and white blood cell number. METHODS: 315 patients with ACS (165 unstable angina pectoris/non-ST-elevation myocardial infarction, 150 ST-elevation myocardial infarction), 111 stable angina (SA) patients, and 296 control subjects were enrolled in the study. All biochemical analyses were carried out using a Hitachi 912 analyzer (Roche). Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined in citrate plasma by ELISA methods. White blood cells (WBC) and fibrinogen were also determined. RESULTS: The plasma concentrations of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, C-reactive protein, fibrinogen, and white blood cells in patients with acute coronary syndrome were significantly elevated compared to the control group (p < 0.001). MMP-9/TIMP-1 ratio was significantly higher in SA and ACS patients (p < 0.001) than controls. Strong positive associations were observed between MMP-9 and TIMP-1 (r = 0.213, p < 0.01), MMP-9 and CRP (r = 0.103, p < 0.01), MMP-9 and fibrinogen (r = 0.299, p < 0.01), MMP-9 and WBC (r = 0.135, p < 0.01), TIMP-1 and CRP (r = 0.219, p < 0.01), TIMP-1 and Fibrinogen (r = 0.226, p < 0.01), TIMP-1 and WBC (r = 0.094, p < 0.1), CRP and fibrinogen (r = 0.158, p < 0.01), CRP and WBC (r = 0.156, p < 0.01, and finally between fibrinogen and WBC (r = 0.234, p < 0.01) in the patients with ACS. CONCLUSIONS: In conclusion, our observations suggest that ACS shows an increase in both remodeling and inflammation markers. In addition, the strong relationship with MMP-9 and inflammatory mediators such as CRP, fibrinogen, and WBC in ACS patients suggests that MMP-9 might be an additional marker and/or consequence of inflammatory components in ACS.

Psoriasis is associated with increased Framingham ten-year risk score for coronary heart disease in Tunisians.

BACKGROUND: To assess the ten-year cardiovascular risk for coronary heart disease (CHD) in psoriatic patients and to test the impact of psoriasis severity and duration on cardiovascular risk. METHODS: A case-control study included 202 adult psoriatic patients and 202 controls. RESULTS: Risk CHD was estimated using the Framingham risk score algorithm. Patients had a higher ten-year Framingham risk score (13.62 +/- 11.86 vs. 9.23 +/- 8.04; p = 0.002) than controls. In addition, a high risk score and a very high risk score (> 40%) were more frequent in psoriatic patients compared with controls (p = 0.043 and p < 0.001, respectively). According to the severity of psoriasis, the ten-year cardiovascular risk increases progressively and significantly (11.84 +/- 10.08; 15.59 +/- 11.79 and 16.92 +/- 14.13 for mild, moderate and severe psoriasis, respectively). CONCLUSIONS: Psoriatic patients have significantly greater risks of developing coronary heart disease than controls in relationship with psoriasis comorbidities such as hypertension, diabetes, dyslipidemia, inflammation and probably with psoriasis itself.

Abnormal circulating levels of matrix metalloproteinases and their inhibitors in diabetes mellitus.

BACKGROUND: The aim of this study was to determine plasma levels of matrix metalloproteinases (MMPs) 2, 3, and 9 and their tissue inhibitors (TIMPs) 1 and 2 in type 2 diabetic patients (T2DM) compared to healthy subjects. METHODS: The study involved 54 patients with T2DM and 57 age and gender matched healthy adults as controls. MMPs 2 and 9 were analyzed by gelatin zymography and MMP-3 and TIMPs 1 and 2 by ELISA. RESULTS: For technical feasibility, MMPs 2 and 9 were expressed in pro forms. Pro-MMP-9 was significantly higher (p < 0.05), whereas TIMP-1 and TIMP-2 levels were significantly decreased (p < 0.01) in patients with T2DM compared to controls. The MMP-3/TIMP-1 and the MMP-3/TMP-2 ratios were significantly higher in T2DM patients than controls (p < 0.05). Fasting plasma glucose was inversely correlated with TIMP-1 (r = -0.412, p < 0.01) and TIMP-2 (r = -0.315, p < 0.001), but was not associated with MMPs. CONCLUSIONS: The present study identified abnormalities in plasma markers for extracellular matrix metabolism in T2DM. The new parameters would constitute an effective approach to explore the complications of uncontrolled diabetes.