Plasma Matrix Metalloproteinase-9 Research Articles

Effects of ultrasound-guided paravertebral block on MMP-9 and postoperative pain in patients undergoing VATS lobectomy: a randomized, controlled clinical trial

BackgroundLocal anesthesia can reduce the response to surgical stress and decrease the consumption of opioids, which may reduce immunosuppression and potentially delay postoperative tumor recurrence. We compared paravertebral block (PVB) combined with general anesthesia (GA) and general anesthesia regarding their effects on postoperative pain and matrix metalloproteinase-9 (MMP-9) after video-assisted thoracoscopic surgery (VATS) lobectomy.Methods54 patients undergoing elective VATS lobectomy at a single tertiary care, teaching hospital located in Qingdao between May 2, 2018 and Sep 28, 2018 were randomised by computer to either paravertebral block combined with general anesthesia or general anesthesia. The primary outcomes were pain scores at rest and on cough at 1, 4, 24, and 48 h after surgery. The secondary outcome were plasma concentrations of MMP-9, complications, and length of postoperative hospital stay.Results75 were enrolled to the study, of whom 21 were excluded before surgery. We analyzed lobectomy patients undergoing paravertebral block combined with general anesthesia (n = 25) or general anesthesia (n = 24). Both groups were similar regarding baseline characteristics. Pain scores at rest at 4 h and 24 h, on cough at 4 h were lower in PVB/GA group, compared with GA group (P < 0.05). There were no difference in pain scores at rest at 1 h, 48 h and on cough at 1 h, 24 h, and 48 h between groups. Patients in the PVB/GA group showed a greater decrease in plasma MMP-9 level at T1 and T2 after VATS lobectomy (P < 0.05). Postoperative complications and length of stay did not differ by anesthetic technique.ConclusionsThe paravertebral block/general anesthesia can provide statistically better pain relief and attenuate MMP-9 response to surgery and after VATS lobectomy. This technique may be beneficial for patients to recover rapidly after lung surgery and reduce postoperative tumor recurrence.Trial registrationChinese Clinical Trial registration number ChiCTR1800016379. Registered 28 May 2018.

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.

Analysis of the association of MPO and MMP-9 with stroke severity and outcome: Cohort study.

In acute cerebral ischemia, circulating neutrophil count and neutrophil-to-lymphocyte ratio (NLR) are positively associated with stroke severity and worse outcomes. Mediators of this effect are unknown. We aimed to investigate (1) the relationship between plasma matrix metalloproteinase-9 (MMP-9) and myeloperoxidase (MPO) concentrations with stroke severity and outcome and (2) MMP-9 and MPO release after ex vivo stimulation of neutrophils by recombinant tissue plasminogen activator (rtPA). We analyzed data collected in 255 patients with supratentorial cerebral infarcts recruited within 48 hours of symptoms onset irrespective of rtPA treatment. The endpoints were excellent outcome (modified Rankin Scale score 0-1), symptomatic intracerebral hemorrhage (European Cooperative Acute Stroke Study-II definition), and death at 3 months. The role of rtPA treatment on peripheral neutrophil degranulation was investigated in 18 patients within 4.5 hours and after 72 hours. Neutrophil counts, NLR, and MPO plasma concentrations, but not MMP-9, were positively correlated with stroke severity. Higher neutrophil counts and NLR were independently associated with worse outcomes and higher mortality rates at month 3. Higher MPO plasma concentrations, but not MMP-9, were associated with worse outcome. Neutrophil-derived MMP-9, after ex vivo rtPA stimulation, but not MPO, were higher after 72 hours in patients treated by IV rtPA but not associated with hemorrhagic transformation. Neutrophil counts, NLR, and MPO plasma concentrations are associated with worse outcome in patients with acute cerebral ischemia, in contrast to MMP-9. Further investigations are needed to deepen our knowledge on MPO's role in the deleterious effect of neutrophils because it could represent a potential therapeutic target.

The analysis of the levels of plasma inflammation-related cytokines and endotoxins in patients with acute aortic dissection.

To investigate the changes in the levels of plasm interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), matrix metalloproteinase-9 (MMP-9) and endotoxins in patients with acute aortic dissection (AAD). 55 AAD patients who were admitted and scheduled to undergo emergency surgery in our hospital from January 2017 to July 2017 were selected and retrospectively analyzed. They were divided into the survival group (n = 40) and the death group (n = 15). The levels of plasma IL-6, TNF-α, CRP, MMP-9 and endotoxins at admission and at 6 h, 12 h and 24 h after admission (T0, T1, T2 and T3) were measured, and the correlations of inflammatory cytokines with endotoxins were analyzed. At T1, T2 and T3, the levels of inflammatory cytokines and endotoxins were increased. The levels of plasma IL-6, TNF-α, CRP, MMP-9 and endotoxins in the death group were significantly higher than those in the survival group at each time point (p < 0.05 in all comparisons). Neutrophil and platelet counts in the death group were higher than those in the survival group (p < 0.05). Correlation analyses indicated that the levels of IL-6, TNF-α, CRP and MMP-9 were positively correlated with the level of endotoxin. Patients with AAD are often accompanied by systemic inflammatory responses, with inflammation-related cytokines (IL-6, TNF-α, CRP and MMP-9) and endotoxins levels significantly elevated. Combined monitoring of dynamic changes in inflammatory cytokines and endotoxins, as well as early interventions, has important clinical implications for evaluating the prognosis of AAD and reducing mortality.

Plasma levels of matrix metalloproteinase-9 (MMP-9) are associated with cognitive performance in patients with schizophrenia.

AimMatrix metalloproteinase‐9 (MMP‐9) has been shown to modulate synaptic plasticity and may contribute to the pathophysiology of schizophrenia. This study investigated the peripheral levels of MMP‐9 and its association with cognitive functions in patients with schizophrenia to see the possible involvement of MMP‐9 in pathophysiology of schizophrenia, especially in cognitive decline.MethodsWe measured the plasma levels of MMP‐9 in 257 healthy controls and 249 patients with schizophrenia, including antipsychotic drug–free patients. We also explored the possible association between plasma MMP‐9 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition (WAIS‐ III), the Wechsler Memory Scale‐Revised (WMS‐R), and the Rey Auditory Verbal Learning Test (AVLT).ResultsWe found that the plasma levels of MMP‐9 were significantly higher in patients with schizophrenia, including antipsychotic drug–free patients, than in healthy controls. We found a significant negative association between plasma MMP‐9 levels and cognitive performance in controls and patients with schizophrenia.ConclusionTogether, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased MMP‐9 levels are associated with cognitive impairment.

Endothelial function and plasma matrix metalloproteinase-2 levels and their association with the size and elastic properties of the ascending aorta in first-degree relatives of bicuspid aortic valve patients.

To explore endothelial function and plasma matrix metalloproteinase-2 levels and their association with the size and elastic properties of the ascending aorta in the first-degree relatives (FDRs) with tricuspid aortic valve (TAV) of individuals with bicuspid aortic valve (BAV). Twenty-six patients with BAV without significant valvular dysfunction, 35 FDRs with TAV, and 29 matched healthy controls were analyzed. Two-dimensional echocardiography and high-resolution ultrasound were applied to evaluate the size and elasticity of the ascending aorta and the flow-mediated vasodilation (FMD) of the brachial artery in response to hyperemia. The aortic diameter was larger in the BAV patients than in the FDRs and controls, and the aortic elastic properties showed larger decreases in the BAV patients. The FDRs had a larger aortic diameter and more impaired elastic properties than the controls. The BAV patients had a significantly lower FMD than the FDRs and controls (P<.001), while the FMD was lower in the FDRs than in the controls (P<.001). The plasma MMP-2 levels were significantly higher in the BAV patients than in the FDRs (P=.001) and controls (P<.001). Additionally, the FDRs had higher plasma MMP-2 levels than the controls (P<.001). Pearson correlation analysis revealed that the aortic diameter, distensibility, stiffness index, and strain were significantly associated with FMD and plasma MMP-2 levels. Aortic enlargement and impaired elasticity in the FDRs with TAV were associated with impaired endothelial function and increased plasma MMP-2 concentrations.

PR3 levels are impaired in plasma and PBMCs from Arabs with cardiovascular diseases.

Cardiovascular disease (CVD) risks persist in patients despite treatment. CVD susceptibility also varies with sex and ethnicity and is not entirely explained by conventional CVD risk factors. The aim of the present study was to identify novel CVD candidate markers in circulating Peripheral blood mononuclear cells (PBMCs) and plasma from Arab obese subjects with and without CVD using proteomic approaches. Human adults with confirmed CVD (n = 208) and matched non-CVD controls (n = 152) living in Kuwait were examined in the present cross-sectional study. Anthropometric and classical biochemical parameters were determined. We employed a shotgun proteomic profiling approach on PBMCs isolated from a subset of the groups (n = 4, each), and differentially expressed proteins selected between the two groups were validated at the mRNA level using RT-PCR (n = 6, each). Plasma levels of selected proteins from the proteomics profiling: Proteinase-3 (PR3), Annexin-A3 (ANX3), Defensin (DEFA1), and Matrix Metalloproteinase-9 (MMP9), were measured in the entire cohort using human enzyme-linked immunosorbent assay kits and were subsequently correlated with various clinical parameters. Out of the 1407 we identified and quantified from the proteomics profiling, 47 proteins were dysregulated with at least twofold change between the two subject groups. Among the differentially expressed proteins, 11 were confirmed at the mRNA levels. CVD influenced the levels of the shortlisted proteins (MMP9, PR3, ANX3, and DEFA1) in the PBMCs and plasma differentially. Despite the decreased levels of both protein and mRNA in PBMCs, PR3 circulating levels increased significantly in patients with CVD and were influenced by neither diabetes nor statin treatment. No significant changes were; however, observed in the DEFA1, MMP9, and ANX3 levels in plasma. Multivariate logistic regression analysis revealed that only PR3 was independently associated with CVD. Our results suggest that the dysregulation of PR3 levels in plasma and PBMCs reflects underlying residual CVD risks even in the treated population. More prospective and larger studies are required to establish the role of PR3 in CVD progression.

Prognostic utility of early plasma matrix metalloproteinases -2 and -9 concentrations after severe traumatic brain injury.

ObjectiveTo determine whether the matrix metalloproteinases-2 and -9 plasma levels were associated with intensive care unit mortality in patients who suffered severe traumatic brain injury, despite the presence of extracerebral injuries.MethodsThis prospective cohort enrolled 39 male patients who suffered severe traumatic brain injury (Glasgow coma scale: 3 - 8 at hospital admission). The plasma matrix metalloproteinase -2 and matix metalloproteinase -9 levels were determined by ELISA at the time of intensive care unit admission.ResultsSevere traumatic brain injury was associated with a 46% intensive care unit mortality rate. Higher plasma matrix metalloproteinase -9 concentrations were associated with mortality: 147.94 ± 18.00ng/mL for survivors and 224.23 ± 23.86ng/mL for nonsurvivors (mean ± standard error of the mean, p = 0.022). In contrast, there was no significant association between matrix metalloproteinase -2 levels and intensive care unit mortality: 315.68 ± 22.90ng/mL for survivors and 336.55 ± 24.29ng/mL for nonsurvivors (p = 0.499). Additionally, there were no significant associations between matrix metalloproteinase -2 (p = 0.711) and matrix metalloproteinase -9 (p = 0.092) levels and the presence of associated lesions.ConclusionIncreased plasma matrix metalloproteinase -9 levels were associated with intensive care unit mortality following severe traumatic brain injury, regardless of the presence of extracerebral injuries. Conversely, in this same context, plasma matrix metalloproteinase -2 levels were not associated with short-term fatal outcome prediction.

Plasma MMP-9, TIMP-1, and TGF-β1 Responses to Exercise-Induced Muscle Injury.

The purpose of this study was to analyze changes in the levels of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and transforming growth factor-β1 (TGF-β1) in response to strength recovery after eccentric exercise in humans. In this study, 16 healthy males participated and were divided into a faster recovery (FR) group (n = 8, >80% of baseline) and a slower recovery (SR) group (n = 8, <40% of baseline) on the basis of their recovery of maximal isometric strength (MIS) 96 h after eccentric exercise. For both groups, measurements were taken of muscle soreness, creatine kinase (CK) activity, and MMP-9, TIMP-1, and TGF-β1 levels during the 24- to 96-h period after eccentric muscle contraction of their non-dominant elbow flexor. Muscle soreness (p < 0.001), CK activity (p < 0.01), and TGF-β1 level (p < 0.01) were significantly lower in the FR group compared with SR group, whereas no significant differences in MMP-9 and TIMP-1 levels were found between the two groups (p > 0.05). These results suggest that scar tissue formation caused by the pro-fibrotic activity of growth factors such as TGF-β1 is a potential cause of delay in strength recovery after exercise-induced muscle injury.

Neuromuscular electrical stimulation in critically ill traumatic brain injury patients attenuates muscle atrophy, neurophysiological disorders, and weakness: a randomized controlled trial

BackgroundCritically ill traumatic brain injury (TBI) patients experience extensive muscle damage during their stay in the intensive care unit. Neuromuscular electrical stimulation (NMES) has been considered a promising treatment to reduce the functional and clinical impacts of this. However, the time needed for NMES to produce effects over the muscles is still unclear. This study primarily aimed to assess the time needed and effects of an NMES protocol on muscle architecture, neuromuscular electrophysiological disorder (NED), and muscle strength, and secondarily, to evaluate the effects on plasma systemic inflammation, catabolic responses, and clinical outcomes.MethodsWe performed a randomized clinical trial in critically ill TBI patients. The control group received only conventional physiotherapy, while the NMES group additionally underwent daily NMES for 14 days in the lower limb muscles. Participants were assessed at baseline and on days 3, 7, and 14 of their stay in the intensive care unit. The primary outcomes were assessed with muscle ultrasound, neuromuscular electrophysiology, and evoked peak force, and the secondary outcomes with plasma cytokines, matrix metalloproteinases, and clinical outcomes.ResultsSixty participants were randomized, and twenty completed the trial from each group. After 14 days, the control group presented a significant reduction in muscle thickness of tibialis anterior and rectus femoris, mean of − 0.33 mm (− 14%) and − 0.49 mm (− 21%), p < 0.0001, respectively, while muscle thickness was preserved in the NMES group. The control group presented a higher incidence of NED: 47% vs. 0% in the NMES group, p < 0.0001, risk ratio of 16, and the NMES group demonstrated an increase in the evoked peak force (2.34 kg/f, p < 0.0001), in contrast to the control group (− 1.55 kg/f, p < 0.0001). The time needed for the NMES protocol to prevent muscle architecture disorders and treat weakness was at least 7 days, and 14 days to treat NED. The secondary outcomes exhibited less precise results, with confidence intervals that spanned worthwhile or trivial effects.ConclusionsNMES applied daily for fourteen consecutive days reduced muscle atrophy, the incidence of NED, and muscle weakness in critically ill TBI patients. At least 7 days of NMES were required to elicit the first significant results.Trial registrationThe trial was registered at ensaiosclinicos.gov.br under protocol RBR-8kdrbz on 17 January 2016.

Role of matrix metalloproteinase-9 gene polymorphisms in glaucoma: A hospital-based study in Chinese patients.

BackgroundGlaucoma is the irreversible vision loss and contributes second leading cause of blindness worldwide. Matrix metalloproteinase‐9 (MMP‐9) is involved with remodeling and destruction of extracellular matrix. Elevated MMP‐9 levels and various functional variants of MMP‐9 have been associated with glaucoma in different population. In the current investigation, we tested association of MMP‐9 common variants with different clinical categories of glaucoma in Chinese population.Materials and MethodsWe enrolled total of 396 glaucoma patients those reported to hospital comprising of 212 primary angle closure glaucoma (PACG) cases and 184 primary open‐angle glaucoma POAG patients. In addition, 329 normal individuals from similar geographical areas were enrolled as healthy controls. Five common single nucleotide polymorphisms (rs3918242, rs3918254, rs2250889, rs3918249, and rs17576) were genotyped by PCR‐RFLP. Plasma levels of MMP‐9 were quantified by ELISA.ResultsHeterozygotes (GC) and allele “G” for rs2250889 polymorphism were more frequent in PACG cases compared with healthy controls (GC: P < .0001, OR = 2.26; G: P < .0001, OR = 1.19). Similarly, heterozygous mutant and minor allele for rs3918242 polymorphism were more prevalent in POAG in comparison with healthy controls. Interestingly, distribution of rs17576 variant was statistically higher in both PACG and POAG cases than healthy controls. Furthermore, analysis of plasma MMP‐9 with MMP‐9 polymorphisms revealed significant association of rs2250889, rs3918242, and rs17576 with plasma levels of the protein.ConclusionsMMP‐9 mutants are associated with elevated plasma MMP‐9 and predisposed to development of glaucoma.

Blocking matrix metalloproteinase-mediated syndecan-4 shedding restores the endothelial glycocalyx and glomerular filtration barrier function in early diabetic kidney disease

The endothelial glycocalyx is a key component of the glomerular filtration barrier. We have shown that matrix metalloproteinase (MMP)-mediated syndecan 4 shedding is a mechanism of glomerular endothelial glycocalyx damage in vitro, resulting in increased albumin permeability. Here we sought to determine whether this mechanism is important in early diabetic kidney disease, by studying streptozotocin-induced type 1 diabetes in DBA2/J mice. Diabetic mice were albuminuric, had increased glomerular albumin permeability and endothelial glycocalyx damage. Syndecan 4 mRNA expression was found to be upregulated in isolated glomeruli and in flow cytometry-sorted glomerular endothelial cells. In contrast, glomerular endothelial luminal surface syndecan 4 and Marasmium oreades agglutinin lectin labelling measurements were reduced in the diabetic mice. Similarly, syndecan 4 protein expression was significantly decreased in isolated glomeruli but increased in plasma and urine, suggesting syndecan 4 shedding. Mmp-2, 9 and 14 mRNA expression were upregulated in isolated glomeruli, suggesting a possible mechanism of glycocalyx damage and albuminuria. We therefore characterised in detail the activity of MMP-2 and 9 and found significant increases in kidney cortex, plasma and urine. Treatment with MMP-2/9 inhibitor I for 21 days, started six weeks after diabetes induction, restored endothelial glycocalyx depth and coverage and attenuated diabetes-induced albuminuria and reduced glomerular albumin permeability. MMP inhibitor treatment significantly attenuated glomerular endothelial and plasma syndecan 4 shedding and inhibited plasma MMP activity. Thus, our studies confirm the importance of MMPs in endothelial glycocalyx damage and albuminuria in early diabetes and demonstrate that this pathway is amenable to therapeutic intervention. Hence, treatments targeted at glycocalyx protection by MMP inhibition may be of benefit in diabetic kidney disease.

Prolong QTc Interval is Associated with Poor Pulse Pressure during Exercise which May Be a Proxy of Arterial Stiffness

The age-associated increase in cardiac and central arterial stiffness is attenuated with lifelong (>25 years) endurance exercise in a dose-dependent manner. Remodelling of the extracellular matrix of cardiovascular structures may underpin these lifelong exercise adaptations in structural stiffness. The primary aim was to examine whether matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) levels are associated with aging and lifelong exercise-related changes in cardiac and central arterial stiffness. Plasma MMPs and TIMPs, left ventricular (LV) (LV stiffness constant) and central arterial stiffness (pulse wave velocity) were examined in healthy adults stratified into five groups based on age and lifelong weekly exercise frequency: (1) young sedentary adults (28–50 years), and older adults (>60 years) who had performed either: (a) sedentary (0–1 sessions/week), (b) casual (2–3 sessions/week), (c) committed (4–5 sessions/week) or (d) athletic (≥6 sessions/week) frequency of exercise. MMP-1 was significantly lower in young compared to older sedentary (p = 0.049). Except for TIMP-2 (p = 0.018 versus committed) and the ratio of MMP-2/TIMP-4 (p = 0.047 versus committed), MMP and TIMP expression was not significantly different in lifelong exercise groups (≥casual) compared to the older sedentary group. MMP-1, -3 had a weak positive relationship with central PWV (r = 0.17–0.25, p ≤ 0.050) but there were no significant relationships between MMPs or TIMPs and LV stiffness constant (p ≥ 0.148). In conclusion, there was not a clear or consistent difference in plasma MMPs and TIMPs with lifelong exercise dose despite exhibiting lower cardiovascular stiffness at the highest exercise levels.

Antibody Microarray Analysis of Plasma Proteins for the Prediction of Histologic Chorioamnionitis in Women With Preterm Premature Rupture of Membranes

We aimed to identify maternal blood biomarkers predictive of histologic chorioamnionitis (HCA) in the plasma of women with preterm premature rupture of membranes (PPROM) and to determine whether the combination of these biomarkers with conventional clinical variables can improve the prediction of HCA. This retrospective cohort study included 82 consecutive women with PPROM (23-34 gestational weeks) who delivered within 96 hours of blood sampling. A membrane-based human antibody microarray was used to analyze the plasma proteome. The validation of 5 candidate biomarkers of interest was performed by enzyme-linked immunosorbent assay (ELISA) in the final cohort (n = 82). Serum C-reactive protein (CRP) levels were measured at sampling. Seventy-nine molecules studied exhibited intergroup differences. Validation by ELISA confirmed higher levels of plasma matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), S100 A8/A9, and insulin-like growth factor-binding protein 1 (IGFBP-1), but not tissue inhibitor of metalloproteinase 1 (TIMP-1), in women with HCA than in women without HCA. Using a stepwise regression analysis, a combined prediction model was developed, which included the plasma MMP-9, serum CRP levels, and gestational age (area under the curve [AUC], 0.932). The AUC for this model was significantly greater than that for any single variable included in the predictive model. Protein-antibody microarray technology can be useful in identifying plasma-based predictors for HCA. This study suggests that plasma MMP-9, IL-6, IGFBP-1, and S100 A8/A9 are important noninvasive predictors for HCA in women with PPROM and that the best predictive model, which combined these biomarkers with conventional clinical factors, can significantly improve the predictability for HCA.

MMP2 Polymorphism Affects Plasma Matrix Metalloproteinase (MMP)-2 Levels, and Correlates with the Decline in Lung Function in Hypersensitivity Pneumonitis Positive to Autoantibodies Patients.

Among hypersensitivity pneumonitis (HP) patients have been identified who develop autoantibodies with and without clinical manifestations of autoimmune disease. Genetic factors involved in this process and the effect of these autoantibodies on the clinical phenotype are unknown. Matrix metalloproteinases (MMPs) have an important role in architecture and pulmonary remodeling. The aim of our study was to identify polymorphisms in the MMP1, MMP2, MMP9 and MMP12 genes associated with susceptibility to HP with the presence of autoantibodies (HPAbs+). Using the dominant model of genetic association, comparisons were made between three groups. For rs7125062 in MMP1 (CC vs. CT+TT), we found an association when comparing groups of patients with healthy controls: HPAbs+ vs. HC (p < 0.001, OR = 10.62, CI 95% = 4.34–25.96); HP vs. HC (p < 0.001, OR = 7.85, 95% CI 95% = 4.54–13.57). This rs11646643 in MMP2 shows a difference in the HPAbs+ group by the dominant genetic model GG vs. GA+AA, (p = 0.001, OR = 8.11, CI 95% = 1.83–35.84). In the linear regression analysis, rs11646643 was associated with a difference in basal forced vital capacity (FVC)/12 months (p = 0.013, β = 0.228, 95% CI95% = 1.97–16.72). We identified single-nucleotide polymorphisms (SNPs) associated with the risk of developing HP, and with the evolution towards the phenotype with the presence of autoantibodies. Also, to the decrease in plasma MMP-2 levels.

Abstract 018: Female Offspring of Polycystic Ovary Syndrome Rat Model Exhibit Insulin Resistance and Tendency Toward Increased Blood Pressure With Aging

Background: Polycystic ovary syndrome (PCOS) is associated with metabolic dysfunction and elevated blood pressure (BP). Whether daughters born to PCOS mothers exhibit a PCOS phenotype is controversial. In addition, whether daughters of PCOS women develop metabolic dysfunction and elevated BP with aging has not been reported. Objectives: The present study tested the hypothesis that aging causes an increase in MAP and metabolic dysfunction in female offspring of PCOS rats (F1 DHT ) along with changes in matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β (TGF-β). Methods: PCOS was induced in SD females by implantation of 5α-dihydrotestosterone pellets (DHT; 7.5 mg/90 days, sc) starting at 4 wks of age. Rats were mated with SD males, and allowed to deliver and lactate. F1 DHT were left untreated and were studied at 14-16 wks or 16-18 mos of age. Control dams were implanted with placebo pellets sc, allowed to mate, deliver and suckle their offspring (F1 PL ). Results: MAP (radiotelemetry) in 14-16 wk F1 DHT females was not different from F1 PL, nor did they exhibit other PCOS characteristics. With aging, F1 DHT rats showed a strong tendency for increased MAP compared to F1 PL (107 ± 4 versus 93 ± 1 mmHg; p = 0.07 (n=2-4)). Plasma MMP-9 and TGF- β1, 2 and 3 were not different between groups. Fasting blood glucose was not different between groups (91 ± 2.6 vs 90 ± 1.6 mg/dl), but F1 DHT rats showed significant hyperinsulinemia (0.9 ± 0.05 vs 0.78 ± 0.03 ng/ml, p ≤ 0.05) and insulin resistance (increased HOMA-IR index; 3.3 ± 0.2 vs 2.8 ± 0.1, p ≤ 0.05, (n = 5-6)). Lean mass (248.3 ± 5.5 vs 241.2 ± 2.5 g), fat mass (38.7 ± 4.8 vs 39.7 ± 2.2 g) and total water (185.8 ± 4.8 vs 179.9 ± 3 g) by Echo MRI, in addition to body weight (310.7 ± 7.7 vs 298.1 ± 4.6 g ; (n = 6-8)) were also not different between groups. Conclusion: MAP in aging female offspring of PCOS rat model tends to be increased along with hyperinsulinemia and insulin resistance with no changes in fasting glucose, lean/fat mass, body weight, MMP9 or TGF-β. The data suggest that women whose mothers had PCOS may be at increased risk for hypertension and metabolic dysfunction with aging, although the mechanisms for the hypertension are not clear.

Correlation of Baseline Plasma and Inguinal Connective Tissue Metalloproteinases and Their Inhibitors With Late High-Pressure Endoleak After Endovascular Aneurysm Repair: Long-term Results

Purpose: To investigate whether plasma and connective tissue matrix metalloproteinases (MMP) and their inhibitors (TIMP) may predict late high-pressure endoleak after endovascular aneurysm repair (EVAR). Materials and Methods: Samples of inguinal fascia and blood were collected in 72 consecutive patients (mean age 73.1 years; 68 men) undergoing primary EVAR with the Endurant stent-graft. Baseline plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 and baseline MMP-2 and MMP-9 activity estimated using gelatin zymography (GZ) were compared between patients who developed late endoleak in follow-up and those who did not. Subgroup analyses were performed between patients with (n=18) and without inguinal hernias and between patients with moderate-diameter (50–59 mm; n=45) or large-diameter (≥60 mm; n=27) abdominal aortic aneurysms (AAA) at primary EVAR. Results: The mean follow-up period was 63.1 months (range 7.5–91.5), during which time 13 (18.1%) patients developed type I (6 Ia and 5 Ib) or 2 type III endoleaks. Only GZ-analyzed proMMP-9 concentrations were higher in the endoleak group than in patients without endoleak (mean difference 8.44, 95% CI −19.653 to −1.087, p=0.03). The patients with primary inguinal hernia at presentation had significantly higher tissue TIMP-2 values (0.8±0.7 vs 0.5±0.4, p=0.018) but lower plasma total (pro- + active) MMP-9 values (11.9±7.8 vs 16.2±7.4, p=0.042) than patients without hernias at the time of EVAR. Patients with AAAs ≥60 mm had significantly higher mean tissue homogenate levels of total (pro- + active) MMP-9 (p=0.025) and total (pro- + active) MMP-2 (p=0.049) as well as higher proMMP-9 (p=0.018) and total (pro- + active) MMP-9 (p=0.021) levels based on GZ compared to patients with moderate-diameter AAAs. Regression analysis revealed a significant association between total (pro- + active) MMP-9 plasma samples and the presence of hernia (OR 0.899, 95% CI 0.817 to 0.989, p=0.029) and between GZ-analyzed proMMP-9 and late endoleak (OR 1.055, 95% CI 1.007 to 1.106, p=0.025). GZ-analyzed proMMP-9 and active MMP-9 were strong predictors of late endoleak in patients with hernia (p=0.012 and p=0.044, respectively) and in patients with AAAs ≥60 mm (p=0.018 and p=0.041 respectively). Conclusion: Inguinal fascial tissue proMMP-9 significantly predicted late endoleak. ProMMP-9 and active MMP-9 biomarkers are significantly associated with late endoleak in hernia patients and in patients with AAAs ≥60 mm. Considering the clinical association between hernia and AAA and the fact that the AAA wall connective tissue environment remains exposed to systemic circulation after EVAR, inguinal fascia extracellular matrix dysregulation and altered MMP activity may reflect similar changes in AAA biology, leading to complications such as endoleak.

Effects of metoprolol combined with trimetazidine on cardiac function and matrix metalloproteinase-9 levels in patients with coronary heart disease complicated with chronic heart failure

Objective To observe the effect of metoprolol combined with trimetazidine on coronary heart disease with chronic congestive heart failure, and its effects on myocardial structure, plasma brain natriuretic peptide (BNP) and matrix metalloproteinase-9 (MMP-9). Methods From January 2016 to November 2017, 160 coronary heart disease patients with chronic congestive heart failure in the First People's Hospital of Wenling were randomly divided into treatment group (78 cases)and control group (77 cases)through random number table method.The control group was given conventional anti-heart failure treatment.The treatment group was treated with metoprolol and trimetazidine.After 3 months of treatment, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume(LVESV), LVEF, BNP and changes in MMP-9 were compared. Results The total effective rate of the treatment group was 90.36%, which was significantly higher than 77.92% of the control group (χ2=5.024, P 0.05), the LVEF of the treatment group was increased[(41.38±9.26)% vs.(46.31±10.8)%] (t=-3.15, P=0.001). After treatment, the LVESV between the treatment group and control group had statistically significant difference[(124.54±16.57)mL vs.(106.36±16.44)mL](t=7.16, P<0.05). The BNP level was decreased in the treatment group after treatment[(4 036.39±696.24)ng/L vs.(3 621.78±732.57)ng/L] (t=3.73, P<0.05), while the BNP level had no statistically significant change in the control group (t=1.47, P=0.07). the MMP-9 level in the treatment group was lower than that before treatment[(396.21±97.56)ng/mL vs.(345.11±86.25)ng/mL](t=3.57, P<0.05), while the MMP-9 level in the control group had no statistically significant change (t=1.06, P=0.15). The MMP-9 and BNP levels decreased more significantly in the treatment group than those in the control group (t=3.73, 3.57, all P<0.05). Conclusion Metoprolol combined with trimetazidine in the treatment of patients with chronic heart failure can significantly alleviate clinical symptoms, reduce the expression level of MMP-9, and is safe for clinical use.Therefore, it is recommended use in clinical. Key words: Congestive heart-failure; Matrix metalloproteinase-9; Ultrasonic cardiogram; Brain natriuretic peptide

Plasma levels of matrix metalloproteinase-9: A possible marker for cold-induced stroke risk in hypertensive rats

The cold weather is associated with an increased occurrence of acute stroke events. However, the underlying mechanisms have not yet been fully elucidated. In the present study, we investigated whether plasma matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels as well as the MMP-9/TIMP-1 ratio could be used as predictor for cold-induced stroke risk in hypertensive rats. A total of 50 male rats were subjected to either control group or 2-kidney, 2-clip (2K – 2C) group (N = 25, each), After blood pressure was stabilized, rats were placed in an intelligent artificial climate chamber and maintained on a 12-h light (22 °C)/dark (4 °C) cycle for 3 days. Plasma levels of MMP-9 and TIMP-1 were measured before and after cold exposure from 50 rats by ELISA. Pretreatment plasma MMP-9 levels were significantly higher in 2K-2C rats than in the controls (P < 0.05), TIMP-1 levels were significantly lower in 2K-2C rats than in the controls (P < 0.05), pretreatment plasma MMP-9 levels were significantly higher in those with cold–induced stroke compared to those without (P < 0.05). Logistic regression analysis showed that only plasma MMP-9 levels remained independently associated with cold–induced stroke after adjusting for potential confounders (OR, 1.17; 95% CI, 1.08 to 1.32; P < 0.007). In contrast, no correlation was observed between systolic blood pressure (SBP), TIMP-1 or MMP-9/TIMP-1 ratio and the cold–induced stroke. Higher plasma MMP-9 levels are significantly correlated with cold-induced stroke in hypertensive rats treated with intermittent cold stress. Plasma MMP-9 may be as a promising biomarker to predict the risk of cold-induced stroke events in hypertensive rats.

Predicted Markers of Overall Survival in Pancreatic Cancer Patients Receiving Dendritic Cell Vaccinations Targeting WT1

Background: We have developed a Wilms’ tumor 1 (WT1)-targeting dendritic cell (DC)-based cancer vaccine combined with standard chemotherapy for patients with advanced pancreatic ductal adenocarcinoma (PDA). Methods: We evaluated predictive markers of overall survival (OS) in PDA patients treated with multiple major histocompatibility complex class I/II-restricted, WT1 peptide-pulsed DC vaccinations (DC/WT1-I/II) in combination with chemotherapy. Throughout the entire period of immunochemotherapy, the plasma levels of soluble factors derived from granulocytes of 7 eligible PDA patients were examined. Moreover, systemic inflammatory response markers (neutrophil-to-lymphocyte ratio [NLR], monocyte-to-lymphocyte ratio [MLR], and granulocyte-to-lymphocyte ratio [GLR]) were assessed. In addition, cytoplasmic WT1 expression in PDA cells was examined. Results: Compared to the 4 non-super-responders (OS <1 year), the remaining 3 super-responders (OS ≥1 year) showed significantly decreased low plasma matrix metalloproteinase-9 levels throughout long-term therapy. The NLR, MLR, and GLR after 5 DC/WT1-I/II vaccinations and 3 cycles of gemcitabine were significantly lower in the super-responders than in the non-super-responders. Furthermore, the cytoplasmic WT1 expression in the PDA cells of super-responders was relatively weak compared to that in the PDA cells of non-super-responders. Conclusions: Prolonged low levels of a granulocyte-related systemic inflammatory response after the early period of therapy and low cytoplasmic WT1 expression in PDA cells may be markers predictive of OS in PDA patients receiving WT1-targeting immunochemotherapy.