Tissue Inhibitor Of Metalloproteinase-1 Ratio Research Articles

Assessment of serum concentrations of matrix metalloproteinases-2, -3 and -9, and tissue inhibitor of metalloproteinases-1 in children with primary hypertension

Introduction: Primary hypertension is regarded to be a growing health concern in children. The pathogenesis of primary hypertension is multifactorial. The role of altered levels of matrix metalloproteinases has been proposed. In hypertension, metalloproteinases are engaged not only in vascular remodelling but also in activation of vasoconstrictive agents. Aim of the study: We aimed at comparing the serum concentrations of matrix metalloproteinases-2, -3 and -9, and tissue inhibitor of metalloproteinases-1 in children with primary hypertension and normotensive peers. Materials and methods: We surveyed 23 children with primary hypertension, aged 14.75 years (median; interquartile range, IQR 3.66) and 23 normotensive subjects, aged 14.66 years (median; IQR 6.25). Serum concentrations of matrix metalloproteinases-2, -3 and -9, and tissue inhibitor of metalloproteinases-1 were measured using enzyme-linked immunosorbent method, and the scores were compared with Mann–Whitney U test, with the level of significance at p ≤ 0.05. Results: In children with primary hypertension, serum concentration of matrix metalloproteinase-2 [178.1 (IQR: 35.84) vs. 99.9 (IQR: 20.1) ng/mL], -3 [6.47 (IQR: 1.75) vs. 2.67 (IQR: 1.08) ng/mL], -9 [191.1 (IQR: 52.75) vs. 58.34 (IQR: 18.99) ng/mL] and tissue inhibitor of metalloproteinases-1 [863.9 (IQR: 192.9) vs. 335.41 (IQR: 109.99) ng/mL] were significantly higher than in the normotensive controls (p < 0.00001). Matrix metalloproteinase-9/tissue inhibitor of metalloproteinases-1 ratio [0.22 (IQR: 0.1) vs. 0.18 (IQR: 0.05)] was also significantly elevated in the hypertensive participants (p = 0.008). Conclusions: Elevated serum concentrations of matrix metalloproteinases-2, -3 and -9, and tissue inhibitor of metalloproteinases-1 in children with primary hypertension may indicate their role in the development of hypertension and/or on the presence of vascular remodelling at an early stage of the disease.

Decreased serum MMP-9 levels in patients with nontraumatic osteonecrosis of the femoral head

BackgroundMatrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) are involved in the pathological mechanism of osteonecrosis of the femoral head (ONFH). This study aimed to investigate the relationship of serum MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio with disease severity in patients with nontraumatic ONFH.MethodsSerum levels of MMP-9 and TIMP-1 among 102 nontraumatic ONFH patients and 96 healthy individuals were determined by enzyme-linked immunosorbent assay (ELISA). Imaging severity was determined using the FICAT classification system. The Harris hip score (HHS) and visual analogue scale (VAS) were used to evaluate clinical progress. The correlations of serum MMP-9 and TIMP-1 levels with imaging severity and clinical progress was evaluated statistically. The diagnostic value of MMP-9 for NONFH disease severity was evaluated by examining receiver operating characteristic (ROC) curves.ResultsThe serum MMP-9 levels and the MMP-9/TIMP-1 ratio were significantly increased in patients with ONFH compared to normal controls, and TIMP-1 levels did not differ between the two groups. Serum MMP-9 levels and the MMP-9/TIMP-1 ratio were positively correlated with FICAT stage and VAS and were negatively correlated with the HHS score. The ROC curve results indicated that MMP-9 could be used as a potential marker of nontraumatic ONFH imaging progression.ConclusionsWe hypothesize that increased MMP-9 expression and an imbalance in the MMP-9/TIMP-1 ratio play a role in the development of ONFH and are correlate with the severity of ONFH. The determination of MMP-9 can be a useful tool to assess the severity of the disease in patients with nontraumatic ONFH.

The usefulness of MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio for diagnosis and assessment of COPD severity

BackgroundInflammation, oxidative stress and an imbalance between proteases and protease inhibitors are recognized pathophysiological features of chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate serum levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with COPD and to assess their relationship with lung function, symptom severity scores and recent acute exacerbations.MethodsIn this observational cohort study, serum levels of MMP-9 and TIMP-1 and the MMP-9/TIMP-1 ratio in the peripheral blood of COPD patients with stable disease and healthy controls were determined, and their association with lung function (postbronchodilator spirometry, body plethysmography, single breath diffusion capacity for carbon monoxide), symptom severity scores (mMRC and CAT) and exacerbation history were assessed.ResultsCOPD patients (n = 98) had significantly higher levels of serum MMP-9 and TIMP-1 and a higher MMP-9/TIMP-1 ratio than healthy controls (n = 47) (p ≤ 0.001). The areas under the receiver operating characteristic curve for MMP-9, TIMP-1 and the MMP-9/TIMP-1 ratio for COPD diagnosis were 0.974, 0.961 and 0.910, respectively (all p < 0.05). MMP-9 and the MMP-9/TIMP-1 ratio were both negatively correlated with FVC, FEV1, FEV1/FVC, VC, and IC (all p < 0.05). For MMP-9, a positive correlation was found with RV/TLC% (p = 0.005), and a positive correlation was found for the MMP-9/TIMP-1 ratio with RV% and RV/TLC% (p = 0.013 and 0.002, respectively). Patients with COPD GOLD 3 and 4 presented greater MMP-9 levels and a greater MMP-9/TIMP-1 ratio compared to GOLD 1 and 2 patients (p ≤ 0.001). No correlation between diffusion capacity for carbon monoxide and number of acute exacerbations in the previous year was found.ConclusionsCOPD patients have elevated serum levels of MMP-9 and TIMP-1 and MMP-9/TIMP-1 ratio. COPD patients have an imbalance between MMP-9 and TIMP-1 in favor of a pro-proteolytic environment, which overall indicates the importance of the MMP-9/TIMP-1 ratio as a potential biomarker for COPD diagnosis and severity.

HUMSCs Restore Uterine Function by Inhibiting Endometrial Fibrosis via Regulation of the MMP-9/TIMP-1 Ratio in CDDP-Induced Injury Rats.

The fertility of females of childbearing age who are cured of cancer by chemotherapy is gradually declining globally. As a broad-spectrum chemotherapy drug in clinic, the damage of cisplatin (CDDP) to female reproductive function cannot be ignored. At present, the study of CDDP damage to the uterus is not sufficient, and the exact mechanism needs to be further explored. Therefore, we conducted this research to determine whether uterine injury in CDDP-induced injury rats might be improved by human umbilical cord mesenchymal stem cells (hUMSCs) and to further explore the precise mechanism. The rat model of CDDP-induced injury was established by intraperitoneal injection of CDDP, and hUMSCs were injected into the tail vein 7 days later. In vivo, uterine function in CDDP-induced injury rats was affected after hUMSC transplantation. In vitro, the specific mechanism was further explored from the cell and protein levels. Overall, the specific reason of CDDP-induced uterine dysfunction in rats was endometrial fibrosis, which was significantly improved after hUMSC transplantation. Further investigation of the mechanism found that hUMSCs could regulate the ratio of matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) in endometrial stromal cells (EnSCs) after CDDP injury.

Effect of spironolactone therapy on the activity of the matrix metalloproteinase system in patients with heart failure after COVID-19

Aim. To assess the change in the activity of the matrix metalloproteinase (MMP) system after 6-month spironolactone therapy in patients with heart failure (HF) with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF) after coronavirus disease 2019 (COVID-19).Material and methods. The study included 90 patients treated at the University Clinical Hospital № 4 of the I.M. Sechenov First Moscow State Medical University with a laboratory-confirmed COVID-19. There were following inclusion criteria: age of 18-85 years; the presence of HFpEF and HFmrEF. The patients were randomized into two groups: group I (n=60) — patients with 6-month spironolactone therapy (25 mg/day) in addition to the standard therapy for HF, spironolactone was taken at a dose of 25 mg/day; Group II (comparison group, n=30) — patients who received standard therapy without spironolactone. All patients were determined plasma MMP concentrations.Results. There were no significant differences in the levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) between the groups when included in the study. A repeated investigation revealed a significant decrease in the concentrations of MMP-9 and TIMP-1 only in group I. In patients of group II, there were no significant changes in the plasma concentrations of MMP-9 and TIMP-1. The MMP-9/TIMP-1 ratio during the initial examination of patients did not have significant differences. After 6-months therapy, a significant decrease in the ratio of MMP-9/TIMP-1 was observed only in patients taking spironolactone.Conclusion. The results obtained confirm a significant decrease in MMP system activity after 6-month spironolactone therapy in patients with HFpEF and HFmrEF after COVID-19. The described antifibrotic effects of spironolactone make it possible to recommend the use of this drug in this category of patients to reduce the negative effect of MMPs on cardiovascular system.

Vaginal Microbiota, Genital Inflammation and Extracellular Matrix Remodelling Collagenase: MMP-9 in Pregnant Women With HIV, a Potential Preterm Birth Mechanism Warranting Further Exploration.

BackgroundPregnant women living with HIV infection (PWLWH) have elevated rates of preterm birth (PTB) in which HIV and cART are implicated. PWLWH also have a high prevalence of adverse vaginal microbiota, which associate with genital tract inflammation. The mechanism underlying PTB in PWLWH is unknown. We present the first data in PWLWH on genital-tract matrix-metalloproteinase-9(MMP-9), an important collagenase implicated in labour onset, and tissue inhibitor of metalloproteinases-1(TIMP-1) and explore correlations with local inflammation and vaginal bacteria.Material and MethodsCervical vaginal fluid (CVF) collected by a soft cup and high vaginal swabs (HVS) were obtained from PWLWH and HIV uninfected pregnant women (HUPW) at three antenatal time points. Maternal characteristics, combination antiretroviral therapy (cART) exposure, and pregnancy outcome were recorded. Concentrations of MMP-9, TIMP-1 and ten cytokines were measured by immunoassays. Vaginal microbiota composition was determined through 16S rRNA amplicon sequencing. MMP-9, TIMP-1 and cytokine concentrations were compared by HIV status, cART, and prematurity and in PWLWH correlations with polymorphonuclear leucocytes, cytokines and bacterial genera were explored.ResultsCVF was available for 50 PWLWH (108 samples) and 12 HUPW (20 samples) between gestation weeks 14-38. Thirty-six PWLWH conceived on cART and 14 initiated post-conception. There were five and one PTB outcomes in PWLWH and HUPW respectively. PWLWH had higher mean CVF concentrations of MMP-9 (p<0.001) and TIMP-1 (p=0.035) in the second trimester compared with HUPW with a similar trend in the third trimester. PWLWH also had higher CVF values of cytokines: IL-1β, IL-8, IL-12 and TNF-α in both trimesters compared to HUPW (p ≤ 0.003). In PWLWH, MMP-9 positively correlated with TIMP-1 (r=0.31, p=0.002) and CVF polymorphonuclear leucocytes (r=0.57, p=0.02). Correlations were observed between MMP-9 and three cytokines: IL-1β (r=0.61), IL-8 (r=0.57) and TNF-α (r=0.64), p<0.001, similarly for TIMP-1. Abundance of anaerobic pathobionts correlated with MMP-9: Gardnerella (r=0.44, p<0.001), Atopobium (r=0.33, p=0.005), and Prevotella genera (r=0.39, p<0.001). Conversely proportion of Lactobacillus genera negatively correlated with MMP-9 (rho=-0.46, p<0.001). MMP-9/TIMP-1 ratio increased with gestational age at sampling in PWLWH, but this was no longer significant after adjusting for confounders and no difference by prematurity was observed in this sub-study.ConclusionsHere we show strong correlations of MMP-9 to genital tract inflammation and sub-optimal bacterial genera in PWLWH indicating the ascending genital tract infection pathway may be a contributory mechanism to the high risk of PTB.

Serum matrix metallopeptidase-9 and tissue inhibitor of metalloproteinase-1 levels may predict response to adrenocorticotropic hormone therapy in patients with infantile spasms

ObjectiveTo evaluate whether serum matrix metallopeptidase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels predict response to adrenocorticotropic hormone (ACTH) therapy in patients with infantile spasms. MethodsWe prospectively evaluated patients with infantile spasms who were referred to Saitama Children’s Medical Center from January 2011 to December 2020. We measured Q-albumin and serum MMP-9 and TIMP-1 levels before ACTH therapy. Patients were divided into three groups based on the etiology of their infantile spasms: those with an unknown etiology and normal development (unknown-normal group); those with a structural and acquired etiology (structural-acquired group); and those with a structural and congenital, genetic, metabolic, or unknown etiology with developmental delay (combined-congenital group). Responders were defined as those having complete cessation of spasms for more than 3 months with the resolution of hypsarrhythmia on electroencephalography during ACTH therapy. ResultsWe collected serum from 36 patients with West syndrome and five patients with infantile spasms without hypsarrhythmia before ACTH therapy. Twenty-three of 41 patients (56.1%) were responders, including 8/8 (100%) in the unknown-normal group, 6/9 (66.7%) in the structural-acquired group, and 9/24 (37.5%) in the combined-congenital group. The serum MMP-9 level and MMP-9/TIMP-1 ratio were significantly higher in responders than in nonresponders (P = 0.001 for both). ConclusionA therapeutic response to ACTH was associated with a higher serum MMP-9 level and higher MMP-9/TIMP-1 ratio in patients with infantile spasms. Therefore, these biomarkers may predict responses to ACTH therapy in this patient population.

Clinical significance of serum matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in the first phase of burn trauma evolution.

No prospective study has specifically examined the serum levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the early shock phase of burn-injured patients. Thus, we aimed to detect early changes, activity dynamics, and the predictive value of MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio to better understand the early repair mechanisms for the development of future therapies for patients with thermal burns. Twenty-five patients with a total body surface area (TBSA) affected by burn <25%, and 30 healthy subjects were enrolled in the study. Serum levels of MMP-9 and TIMP-1 were determined by the ELISA method. Our results showed that MMP-9 concentrations increased immediately after injury and remained on a plateau. In contrast, TIMP-1 showed an upward trend throughout the 7-day study period, and the time course of the MMP-9/TIMP-1 ratio followed the inverse dynamics of TIMP-1. Analysis of the areas under the receiver operating characteristic (ROC) curves (AUC) showed that patients with burn wounds tended to have a MMP-9 value higher than 421.5 ng/ml (AUC=0.979), TIMP-1 value higher than 231.6 ng/ml (AUC=0.908), and MMP-9/TIMP-1 ratio higher than 2.31 (AUC=0.959) (P<0.001). Our findings suggest that although the variations in the two biomarkers were different regarding the time of the initial insult, their ratio is a specific and sensitive indicator of burn evolutivity in patients with a TBSA affected by a burn <25%.

Age-associated level of myocardial fibrosis markers and chemokines in patients with acute coronary syndrome

Aim. To study age-related specifics of the concentration of fibrosis markers and monocyte chemotactic protein-1 (MCP-1) in patients with ST-segment elevation acute coronary syndrome (STE-ACS).Material and methods. A total of 140 STE-ACS patients were examined. Depending on the age, participants were divided into following groups: middle age — 42 patients, elderly — 50 patients, senile — 48 patients. The control group (CG) consisted of 20 people without cardiovascular disease. The level of matrix metallopeptidase 9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), MCP-1 was determined by enzyme immunoassay. Statistical processing was carried out using the MATLAB 2020software.Results. It was found that in STE-ACS patients, the MMP-9 level in middle-aged patients is 2,9 times higher than in the CG (p&lt;0,001), elderly — 4,1 times (p&lt;0,001), senile — 6 times (p&lt;0,001). A strong direct relationship was found between age and MMP-9 level (r=0,86088, p&lt;0,001). The TIMP-1 level was higher in all patients (p&lt;0,05) compared with CG. A strong direct relationship was found between levels of MMP-9 and TIMP-1 (r=0,7801; p&lt;0,01). The MMP-9/TIMP-1 ratio was higher in the group of middle-aged people by 85,7% (p&lt;0,05), elderly — 1,2 times (p&lt;0,001), senile — 2,3 times (p&lt;0,001) compared to CG. MCP-1 was elevated in all age groups (p &lt;0,001). A direct correlation was found between levels of MCP-1 and MMP-9 (r=0,726, p&lt;0,001).Conclusion. In STE-ACS patients, an age-associated increase in concentrations of MMP-9 and MMP-9/TIMP-1 ratio was found in comparison with CG, which indicates the predominance of intercellular matrix degradation marker in patients with ACS. At the same time, MMP-9 increase is possibly induced by MCP-1.

Matrix metalloproteinase MMP-8, TIMP-1 and MMP-8/TIMP-1 ratio in plasma in methicillin-sensitive Staphylococcus aureus bacteremia.

BackgroundMatrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have been shown to predict prognosis in sepsis. However, MMP-8 and TIMP-1 in Staphylococcus aureus bacteremia (SAB) lacks evaluation and their role in the pathogenesis of SAB is unclear.MethodsMMP-8 and TIMP-1 and MMP-8/TIMP-1 molar ratio were determined at days 3, 5 and 28 from positive blood cultures in patients with methicillin-sensitive SAB and the connection to disease severity and early mortality was determined.ResultsAltogether 395 SAB patients were included. Patients with severe sepsis or infection focus presented higher MMP-8 levels at day 3 and 5 (p<0.01). Higher day 3 and 5 MMP-8 levels were associated to mortality at day 14 and 28 (p<0.01) and day 90 (p<0.05). Day 3 MMP-8 cut-off value of 203 ng/ml predicted death within 14 days with an area under the curve (AUC) of 0.70 (95% CI 0.57–0.82) (p<0.01). Day 5 MMP-8 cut-off value of 239 ng/ml predicted death within 14 days with an AUC of 0.76 (95% CI 0.65–0.87) (p<0.001). The results for MMP-8/TIMP-1 resembled that of MMP-8. TIMP-1 had no prognostic impact. In Cox regression analysis day 3 or 5 MMP-8 or day 3 MMP-8/TIMP-1 had no prognostic impact whereas day 5 MMP-8/TIMP-1 predicted mortality within 14 days (HR, 4.71; CI, 95% 1.67–13.3; p<0.01).ConclusionMMP-8 and MMP-8/TIMP-1 ratio were high 3–5 days after MS-SAB diagnosis in patients with an infection focus, severe sepsis or mortality within 14 days suggesting that matrix metalloproteinase activation might play a role in severe SAB.

Angiotensin-converting enzyme inhibitors increase anti-fibrotic biomarkers in African Americans with left ventricular hypertrophy.

Angiotensin‐converting enzyme inhibitors (ACEi) are part of the indicated treatment in hypertensive African Americans. ACEi have blood pressure‐independent effects that may make them preferred for certain patients. We aimed to evaluate the impact of ACEi on anti‐fibrotic biomarkers in African American hypertensive patients with left ventricular hypertrophy (LVH). We conducted a post hoc analysis of a randomized controlled trial in which hypertensive African American patients with LVH and vitamin D deficiency were randomized to receive intensive antihypertensive therapy plus vitamin D supplementation or placebo. We selected patients who had detectable lisinopril (lisinopril group) in plasma using liquid‐chromatography/mass spectrometry analysis and compared them to subjects who did not (comparison group) at the one‐year follow‐up. The pro‐fibrotic marker type 1 procollagen C‐terminal propeptide (PICP) and the anti‐fibrotic markers matrix metalloproteinase‐1 (MMP‐1), tissue inhibitor of metalloproteinases 1 (TIMP‐1), telopeptide of collagen type I (CITP), and N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) peptide were measured. Sixty‐six patients were included, and the mean age was 46.2 ± 8 years. No difference was observed in the number and intensity of antihypertensive medications prescribed in each group. Patients with detectable lisinopril had lower blood pressure than those in the comparison group. The anti‐fibrotic markers Ac‐SDKP, MMP‐1, and MMP‐1/TIMP‐1 ratio were higher in patients with detectable ACEi (all p < .05). In a model adjusted for systolic blood pressure, MMP‐1/TIMP‐1 (p = .02) and Ac‐SDKP (p < .001) levels were associated with lisinopril. We conclude that ACEi increase anti‐fibrotic biomarkers in hypertensive African Americans with LVH, suggesting that they may offer added benefit over other agents in such patients.

The antihypertensive agent hydralazine reduced extracellular matrix synthesis and liver fibrosis in nonalcoholic steatohepatitis exacerbated by hypertension.

Hypertension is an important risk factor for nonalcoholic steatohepatitis. We have previously demonstrated that hypertensive rats fed a high fat and cholesterol (HFC) diet incurred a more severe hepatic inflammatory response and fibrosis. Here we investigated the role of hypertension in NASH by comparing HFC-induced hepatic fibrogenesis between spontaneously hypertensive rats (SHRs) and their normotensive Wistar Kyoto counterpart. Compared to the counterpart, the HFC diet led to stronger aggregation of CD68-positive macrophages in SHRs. HFC feeding also resulted in significantly higher upregulation of the fibrosis-related gene alpha-smooth muscle actin in SHR. The HFC diet induced higher overexpression of serum tissue inhibitor of metalloproteinase-1 (TIMP1) and greater suppression of matrix metalloproteinase-2 (MMP2):TIMP1, MMP8:TIMP1, and MMP9:TIMP1 ratios, as a proxy of the activities of these MMPs in SHR. Administration of the antihypertensive agent hydralazine to SHRs significantly ameliorated HFC-induced liver fibrosis; it suppressed the aggregation of CD68-positive macrophages and the upregulation of platelet-derived growth factor receptor beta, and collagen, type 1, alpha-1 chain. In conclusion, a hypertensive environment exacerbated the hepatic fibrogenetic effects of the HFC diet; while the effects were partially reversed by the antihypertensive agent hydralazine. Our data suggest that antihypertensive drugs hold promise for treating NASH exacerbated by hypertension.

Molecular biomarker profile of heart failure with mid-range and preserved ejection fraction in patients with type 2 diabetes

Aim. To study molecular biomarkers in patients with type 2 diabetes (T2D) in combination with heart failure with preserved (HFpEF) and mid-range ejection fraction (HFmrEF) and compare the data obtained with clinical characteristics of myocardial remodeling.Material and methods. The study included 42 patients with T2D (men — 53%, mean age — 60 years) with clinical manifestations of class II HF: 29 patients with HFpEF (group 1) and 13 patients with HFmrEF (group 2). The control group consisted of 13 healthy people, which were comparable in sex and age and had a normal body mass index (BMI). Patients received stable glucose-lowering and optimal drug therapy for HF for 3 months prior to enrollment in the study. Patients with HFpEF and HFmrEF were comparable in clinical and demographic parameters, had glycated hemoglobin (HbA ) of 8,5% and 8,8%, respectively (p&gt;0,05), increased BMI or grade I-II obesity.We studied following biomarkers: NT-proBNP, highly sensitive C-reactive protein (hsCRP), sST2, galectin-3, procollagen type I C-terminal propeptide (PICP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1).Results. Volumetric parameters of the left ventricle (LV),LV mass indexed to growth and NT-proBNP were higher in the group of HFpEF patients (p&lt;0,05 for all). The concentrations of galectin-3, PICP were higher, and the MMP-9/TIMP-1 ratio decreased in patients with T2D compared with the control group (p&lt;0,05 for all). PICP values were higher in patients with HFmrEF compared with patients with HFpEF (106,4 (85,4; 140,4) ng/ml vs 46,8 (12,6; 98,6 ng/ml), respectively, p=0,043). In patients with T2D and HF, a relationship was found between TIMP-1 andLV end-diastolic volume (r=-0,68; p=0,042).Conclusion. Patients with HFmrEF and T2D have higherLV volume and mass, higher concentrations of NT-proBNP and PICP in comparison with patients with HFpEF. The direction of MMP-9/TIMP-1 changes may reflect a decrease in antifibrotic processes. Further prospective studies on large samples using a multiple biomarker model are required in T2D and various HF phenotypes.

Extracellular matrix collagen biomarkers levels in patients with chronic thromboembolic pulmonary hypertension.

Limited data exist on changes in the extracellular matrix (ECM) collagen biomarkers levels during chronic thromboembolic pulmonary hypertension (CTEPH) development. This study aimed to investigate ECM collagen biomarkers levels in stable patients with CTEPH. Patients with CTEPH and healthy persons were enrolled. Serum levels of procollagen III N-terminal peptide (PIIINP), carboxyterminal propeptide of type I procollagen (PICP), matrix metalloproteinases (MMP2), MMP9, and tissue inhibitor of metalloproteinases 1(TIMP1) were measured by ELISA. Clinical data coincident with samples were collected. The pulmonary endarterectomy (PEA) and control pulmonary artery tissue samples were analyzed for genetic and immunohistochemical differences. The serum concentrations of PIIINP, PICP, MMP2, and MMP9 decreased significantly in CTEPH patients compared to healthy controls (P < 0.001 for each). CTEPH patients had higher serum concentrations of TIMP1 (median, 111.97 [interquartile range, 84.35-139.93]) compared to healthy controls (74.97 [44.03-108.45] ng/mL, P < 0.001). The MMP2 to TIMP1 ratio was lower in patients than in the controls (P < 0.001). After adjusting for the body mass index (BMI), the MMP2 to TIMP1 ratio correlated negatively with pulmonary vascular resistance (PVR) (r = - 0.327, P = 0.025). Increased TIMP1 (P = 0.04) gene expression was identified in tissues of CTEPH patients. Immunohistochemistry results of vascular walls substantiated qRT-PCR results. This study indicates that ECM collagen biomarkers levels were significantly different in stable patients with CTEPH and healthy controls with significantly increased TIMP1 and decreased MMP2 and MMP9. Differences in TIMP1 expression should be expected not only among healthy controls and patients serum, but also across pathological tissue regions. These findings suggest that the state of vascular remodeling in pulmonary vascular bed in stable patients may be represented by ECM collagen biomarkers levels. We conclude that TIMP1 may play an important role in pulmonary vascular reconstruction in stable CTEPH patients.

Hepatoprotective effect and possible mechanism of phytoestrogen calycosin on carbon tetrachloride-induced liver fibrosis in mice.

The study was to explore the hepatoprotective effect and possible mechanism of calycosin on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Hepatic fibrosis was induced by intraperitoneal injection of CCl4 in C57BL/6 male mice. Serum alanine aminotransferase (ALT) and aspartate transaminase (AST) activity, superoxide dismutase (SOD) activity, and hydroxyproline (Hyp) and malondialdehyde (MDA) levels were determined by biochemical assays. Liver histopathology was assessed by H&E and Masson trichrome staining. The mRNA expressions of α-smooth muscle actin (α-SMA), collagen-I (Col-I), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were determined using qRT-PCR. The protein levels of α-SMA, Col-I, estrogen receptor α (ERα), estrogen receptor β (ERβ), tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-1 (MMP-1), JAK2, phospho-JAK2 (p-JAK2), STAT3, and phospho-STAT3 (p-STAT3) were detected by Western blotting. The levels of α-SMA and ERβ were measured by immunohistochemistry. Calycosin significantly reduced liver index, MDA level, and ALT and AST activity and increased SOD activity. The α-SMA, Col-I, and Hyp of the calycosin group were significantly lower than those of the model group. Calycosin increased MMP-1 and inhibited TIMP-1 expression resulting in the improvement of MMP-1/TIMP-1 ratio. Importantly, calycosin improved ERβ protein expression, JAK2 and STAT3 mRNA expressions, p-JAK2/JAK2, and p-STAT3/STAT3 relative protein expressions. However, ERα, JAK2, and STAT3 protein expressions were relatively unchanged. Calycosin significantly inhibits liver fibrosis in mice, and its mechanism may involve the following: calycosin inhibits oxidative stress; calycosin inhibits collagen synthesis and balances MMP-1/TIMP-1 system; calycosin increases ERβ expression and activates JAK2-STAT3 pathway.

Plasma Levels of Matrix Metalloprotease MMP-9 and Tissue Inhibitor TIMP-1 in Caucasian Patients with Polypoidal Choroidal Vasculopathy

Background: Matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) are regulating enzymes of the extracellular matrix. A systemic imbalance of MMP-9 and TIMP-1, thought to reflect an imbalance of the extracellular matrix homeostasis, is previously associated with polypoidal choroidal vasculopathy (PCV) in Asian patients. Previous studies suggest inter-ethnical differences in the genetic background and etiology of PCV. To further explore this issue, we studied the plasma levels of MMP-9 and TIMP-1 in Caucasian patients with PCV and compared to healthy age-matched controls. Methods: For this prospective case-control study, 60 participants were recruited who were either patients with PCV (n = 26) or healthy controls (n = 34). All participants underwent detailed clinical examination. We sampled fresh venous blood, isolated plasma, and quantified plasma concentrations of the extracellular matrix regulators MMP-9 and TIMP-1 using electrochemiluminescence immunoassays. Results: Plasma levels of MMP-9 (p = 0.4), TIMP-1 (p = 0.9), and MMP-9/TIMP-1 ratio (p = 0.4) did not differ significantly between patients with PCV and healthy controls. No differences appeared after adjusting for influencing co-variates in multivariate analyses. Conclusion: We demonstrate that Caucasian patients with PCV do not have altered levels of plasma MMP-9 or plasma TIMP-1. These findings suggest no strong evidence of a systemic imbalance of the extracellular matrix homeostasis in Caucasian patients with PCV. Our findings are in line with studies of other aspects of PCV that are also subject to significant inter-ethnical differences.

Plasma Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 as Prognostic Biomarkers in Critically Ill Patients.

Matrix metalloproteinase 9 (MMP-9) plays an important role in inflammatory and pathological processes by enabling the inflow of leukocytes to the site of infection or tissue damage. MMP-9 and tissue inhibitor of metalloproteinase 1 (TIMP-1) have been described as potential prognostic biomarkers in various clinical settings. The aim of the study was to evaluate the usefulness of plasma levels of MMP-9 and TIMP-1 as well as the MMP-9/ TIMP-1 ratio in predicting the outcome in patients admitted to the intensive care unit (ICU). The study included 56 critically ill patients with multiple organ failure. Plasma levels of MMP-9 and TIMP-1 were determined on hospitalization day 1, 2, 3 and 7. Nineteen (35.7%) patients died. The level of TIMP-1 was statistically significantly higher on day 1 and 7 of hospitalization in non-survivors, as compared to survivors (p=0.01). A statistically significant positive correlation was found between MMP-9 and TIMP-1. The MMP-9/TIMP-1 ratio was comparable in both groups during of observation (0.62 on day 1). The MMP-9/TIMP-1 ratio was positively correlated with the level of lactate and negatively correlated with platelet count. Likewise, TIMP-1 was positively correlated with the level of lactate. The level of MMP-9 was higher in the non-survivor group only on day 7 of observation. In conclusion, although TIMP-1 and MMP-9 concentrations were higher in non-survivors and the MMP-9/TIMP-1 ratio was related to some parameters of critical illness, further research is needed to verify whether they can serve as reliable biomarkers for early prognostication of ICU patients.

Levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 are related to cardiopulmonary injury in fetal inflammatory response syndrome

OBJECTIVES:To evaluate the diagnostic value of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and the MMP-9/TIMP-1 ratio in fetal inflammatory response syndrome (FIRS), and determine a possible association with the incidence of bronchopulmonary dysplasia (BPD) and myocardial injury.METHODS:Overall, 61 cases of preterm infants with FIRS were divided into the FIRS group 1 (≤32 weeks) and FIRS group 2 (32 to 37 weeks). Similarly, 57 cases of normal preterm infants were divided into Control group 1 and Control group 2. Levels of interleukin-6 (IL-6), MMP-9, and TIMP-1 were detected by enzyme-linked immunosorbent assay. Spearman’s linear correlation was used to analyze the relationship between dependent variables. Pathological changes were examined by hematoxylin and eosin (HE) staining and in amniotic fluid smears.RESULTS:Levels of IL-6, MMP-9, and TIMP-1, and the MMP-9/TIMP-1 ratio were significantly higher in the FIRS group than in the Control groups. IL-6 was positively correlated with MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio. Areas under the curve (AUC) of MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio were 0.92, 0.90, and 0.95, respectively. HE staining and amniotic fluid smears showed the aggregation of inflammatory cells. MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio were closely related to the incidence of BPD (≤32 weeks) and myocardial injury (<37 weeks) in preterm infants.CONCLUSION:MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio revealed a certain diagnostic value for FIRS; combined with gestational age, these parameters were effective for predicting cardiopulmonary injury.

Serum matrix metallopeptidase-9 and tissue inhibitor of metalloproteinase-1 levels in autoimmune encephalitis

ObjectiveSome pediatric patients with autoimmune encephalitis (AE) experience sequelae in spite of immunotherapy. In this study, we aimed to evaluate the association of serum matrix metallopeptidase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels with the neurological prognosis of AE. MethodsWe retrospectively included 13 patients with AE who had been referred to Saitama Children’s Medical Center from February 2011 to May 2019. We compared serum MMP-9 levels, TIMP-1 levels, and MMP-9/TIMP-1 ratio in the acute period (within 30 days from the onset of AE) and subacute period (30-day period following the acute period). We also compared these biomarker levels between patients with (group A) and without sequelae (group B). Sequelae were evaluated at discharge or the last visit. ResultsGroup A (median age, 7.8 years; range, 5.3–10.7 years) and group B (median age, 13.3 years; range, 11.1–15.4 years) had 6 patients each; 1 patient was excluded because the time of AE onset was unknown. In the acute period, there were no significant differences in MMP-9 levels, TIMP-1 levels, and MMP-9/TIMP-1 ratio between groups A and B. In the subacute period, serum MMP-9/TIMP-1 ratio was higher in group A than in group B (p < 0.01). There were no significant differences in MMP-9 and TIMP-1 levels between groups A and B. ConclusionsPatients with sequelae of AE showed a high MMP-9/TIMP-1 ratio in the subacute period. Our study demonstrates that elevation of serum MMP-9/TIMP-1 ratio in the subacute period may be a predictive factor of sequelae of AE.

Melatonin protects blood-brain barrier integrity and permeability by inhibiting matrix metalloproteinase-9 via the NOTCH3/NF-κB pathway.

The pathophysiological mechanism of white matter hyperintensities of cerebral small vessel disease (CSVD) includes an impaired blood-brain barrier (BBB) with increased permeability. Neuroinflammation likely contributes to the disruption of the BBB in CSVD. Therefore, understanding the molecular mechanism of how neuroinflammation causes BBB damage is essential to preventing BBB disruption in CSVD. Matrix metalloproteinase 9 (MMP-9) contributes to BBB damage in neuroinflammatory diseases. In this study, we observed that interleukin-1β (IL-1β)-induced MMP-9 secretion in pericytes increased BBB permeability to sodium fluorescein (Na-F) by damaging the disruption of VE-cadherin, occludin, claudin-5, and zonula occludin-1 (ZO-1). Melatonin reduced BBB permeability to Na-F and inhibited the disruption of the adherens and tight junction proteins. Melatonin also downregulated MMP-9 and upregulated tissue inhibitor of metalloproteinases 1 (TIMP-1) gene expression, which decreased the MMP-9/TIMP-1 ratio. In addition, nuclear translocation of NF-κB/p65 induced by IL-1β in pericytes upregulated MMP-9 expression, which was inhibited by the NF-κB inhibitor PDTC. However, the NOTCH3 inhibitor DAPT significantly inhibited NF-κB/p65 translocation to the nucleus, while melatonin in combination with DAPT significantly prevented NF-κB/p65 translocation than DAPT alone. Our results suggest that melatonin reduced MMP-9-induced permeability of the BBB. Melatonin reduced MMP-9 expression and activity, which was induced by IL-1β through the regulation of the NOTCH3/NF-κB signaling pathway in pericytes, suggesting that pericytes regulate BBB integrity and function.