Plasma Matrix Metalloproteinase-9 Levels Research Articles

Exploring the Role of MMP-9 and MMP-9/TIMP-1 Ratio in Subacute Stroke Recovery: A Prospective Observational Study.

Despite the significant changes that unfold during the subacute phase of stroke, few studies have examined recovery abilities during this critical period. As neuroinflammation subsides and tissue degradation diminishes, the processes of neuroplasticity and angiogenesis intensify. An important factor in brain physiology and pathology, particularly neuroplasticity, is matrix metalloproteinase 9 (MMP-9). Its activity is modulated by tissue inhibitors of metalloproteinases (TIMPs), which impede substrate binding and activity by binding to its active sites. Notably, TIMP-1 specifically targets MMP-9 among other matrix metalloproteinases (MMPs). Our present study examines whether MMP-9 may play a beneficial role in psychological functions, particularly in alleviating depressive symptoms and enhancing specific cognitive domains, such as calculation. It appears that improvements in depressive symptoms during rehabilitation were notably linked with baseline MMP-9 plasma levels (r = -0.36, p = 0.025), and particularly so with the ratio of MMP-9 to TIMP-1, indicative of active MMP-9 (r = -0.42, p = 0.008). Furthermore, our findings support previous research demonstrating an inverse relationship between pre-rehabilitation MMP-9 serum levels and post-rehabilitation motor function. Crucially, our study emphasizes a positive correlation between cognition and motor function, highlighting the necessity of integrating both aspects into rehabilitation planning. These findings demonstrate the potential utility of MMP-9 as a prognostic biomarker for delineating recovery trajectories and guiding personalized treatment strategies for stroke patients during the subacute phase.

Plasma levels of matrix metalloproteinases in patients with breast cancer as a potential marker of cardiotoxicity associated with doxorubicin therapy

Plasma levels of matrix metalloproteinases in patients with breast cancer as a potential marker of cardiotoxicity associated with doxorubicin therapy

The correlation between pentraxin-3, matrix metalloproteinase-9, and estimated glomerular filtration rate in patients with chronic kidney disease

Background: Chronic kidney disease (CKD) is diagnosed when there is a sustained decrease in the estimated glomerular filtration rate (EGFR) over a period of more than 3 months. While Pentraxin-3 (PTX-3) and Matrix Metalloproteinase-9 (MMP-9) levels increase during the acute phase of the kidney injury, chronic conditions often exhibit alteration in the epithelial mesenchymal transition (EMT).Objectives: This study aimed to elucidate the correlation between serum PTX-3, MMP-9, and eGFR in patients with CKD. Method: Thirty hypertensive patients with CKD stages 3, 4, and 5, aged between 16 and 65 years, were enrolled in the study (15 males and 15 females). Diagnosis of CKD was based on the 2012 Kidney Disease Improving Global Outcomes (KDIGO) criteria, utilizing serum creatinine, and CKD-epidemiology Collaboration (CKD-EPI) estimates. Subsequently, serum MMP-9 and PTX-3 levels were quantified. Result: Patients with CKD exhibited significantly higher serum levels of PTX3 and MMP9. Furthermore. a significant negative connection between PTX-3, MMP-9, and EGFR was observed. Additionally, CKD patients displayed a correlation between PTX-3 and MMP-9 concentrations.Conclusion: Plasma levels of PTX-3 and MMP-9 serve as unique, promising, and important markers that contribute to the pathogenesis of CKD.

Abstract 2444: Plasma levels of matrix metalloproteinases 8 are significantly increased in patients with colorectal cancer (CRC) and mRNA levels are increased in 71% of tumors vs normal tissue

Abstract Introduction: Matrix metalloproteinases 8 (MMP-8) is a member of the MMP protease family mainly involved in degrading extracellular matrix. A variety of cells express MMP-8 and during pathological inflammation neutrophils release IL-1, IL-8, TNF-α, and GM-CSF which triggers MMP-8 secretion. MMP-8 aids tumors in evading immune detection during the development of CRC and also regulates the role of endothelial cell in angiogenesis. Increased MMP-8 tumor expression and serum levels has been noted in hepatocellular cancer and melanoma patients and are associated with adverse outcomes. There is limited data regarding blood levels of MMP-8 in CRC patients. This study compared preoperative (PreOp) plasma MMP-8 levels in patients with CRC and benign colonic pathology (BCP) undergoing bowel resection. Method: Patients with CRC or BCP who had elective colorectal resection who were enrolled in an IRB approved tissue and data bank for whom preop plasma samples were available were eligible. Data analyzed included demographic, clinical, operative, and final pathology reports. Blood specimens were quickly processed and plasma stored at -80°C. MMP-8 levels in Preop plasma samples were measured via ELISA, in duplicate, and reported as median +95% CI (ng/ml). MMP8 expression was examined in paired CRC and normal mucosal tissue samples from a subset of the CRC patients (n=20) via QRT-PCR. Immunohistochemistry (IHC) was conducted on formalin-preserved tissue sections (tumor/normal pairs) following standard protocols. The concept of MMP8 as CRC diagnostic marker was evaluated by assessing the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC). The analysis was done with the Mann-Whitney test (significance, p<0.05). Results: 96 CRC patients (74% colon and 26% rectal cancer) and 96 BCP patients (32% adenoma, 64% diverticulitis, 4% other) met entry criteria. The CRC stage distribution was: Stage 1, 26%; Stage 2, 26% Stage 3, 40%; and stage 4, 8%. Median plasma MMP-8 levels were higher in CRC (8.21, CI: 6.92, 10.81) compared to BCP patients (5.59, CI: 4.68, 7.30; p<0.001). A non-significant increase in median MMP-8 levels were noted in STG IV vs STG I and STG II and STG III was found (38-89%). IHC validated the expression of MMP-8 in CRC tumors relative to normal colon. Increased expression of MMP-8 was seen in 71% of the tested CRC samples (12/17). The AUC value for the ROC curve was 0.653 (sensitivity 35%, specificity 0.95%). Conclusion: The median MMP-8 level in CRC patients was found to be 47% higher compared to BCP patients and 89% higher in stage IV vs stage II patients (p=0.06). The tumor is the most likely the cause of elevated plasma levels. Increased tumor expression of MMP-8 mRNA was noted in 71% of tumors. The low sensitivity of the ROC curve suggests MMP8 alone has no value as diagnostic factor. Larger studies are justified. Citation Format: Chandana S. K. Herath Mudiyanselage, Anuj R. Sharma, Neil Mitra, Aashutosh Sah, Xiaohong Yan, Pablo Palacios, Vesna Cekic, Richard L. Whelan. Plasma levels of matrix metalloproteinases 8 are significantly increased in patients with colorectal cancer (CRC) and mRNA levels are increased in 71% of tumors vs normal tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2444.

Abstract 5392: Plasma levels of Matrix metalloproteinases 9, an angiogenic promoting protein, are persistently elevated three weeks after minimally invasive colorectal resection (MICR) for cancer which may support residual tumor metastasis

Abstract Introduction: The Matrix metalloproteinases (MMPs) family are a collection of zinc and calcium-dependent endopeptidases. MMP-9 is instrumental in modifying the extracellular matrix (ECM) and generating bioactive molecules which influence a range of physiological functions. Cellular TNF-a, IL-8, VEGF, and FGF-2 can stimulate the production of MMP-9 in endothelial cells (EC), a process that controls healthy and disease-related angiogenesis. MMP-9 facilitates tumor metastasis and also is involved with wound healing. MMP-9 is generated by white blood cells, ECs, and several other cells. There’s a significant increase in plasma MMP-9 levels in patients suffering from colorectal cancer (CRC). The aim of this study was to assess plasma MMP-9 levels before and during the first month following MICR for CRC. Method: CRC patients enrolled in an IRB approved data/plasma bank who had undergone MICR for whom plasma samples were available from the following time points were deemed eligible for this study; preoperatively (PreOp) and on Postoperative Day (POD) 1, POD 3 and at least 1 later postop timepoint (POD 7-41). The demographic, clinical operative and pathology reports were reviewed. Blood specimens were collected, processed, and frozen. MMP-9 levels were measured in duplicate via ELISA. The Wilcoxon paired t-test was used for analysis and significance set at p<0.05. Results: 86 CRC MICR patients (69% colon,31% rectal; laparoscopic 69%, hand-assisted 31%; 47 males, 39 females; mean age 63.9± 14.3 years), met the entry criteria. The mean hospital stay was 6.5±3.0 days. The cancer stages were distributed as follows: stage I; (n=26), II; (n=25), III; (n=30), and IV; (n=4). Compared to the mean preop MMP-9 plasma levels (155.3±132.1,n=86; ng/ml), there was a significant increase on postoperative day (POD) 1 (292.6± 213.0; n=86, p<0.001), POD3 (232.1±205.9,n=78, p<0.01), POD7-13 (217.8±171.2, n=63, p<0.01), POD14-20 (228.7± 109.1,n=24,p=03). No difference was found at the POD 21-41 time points vs preop results. Non-significant increases in plasma MMP-9 levels were noted in the hand-assisted surgery group during the POD 3-27 period compared to the laparoscopic group. Conclusion: Postop plasma MMP-9 levels were significantly elevated (20% - 88%) vs preop levels for 3 weeks after MICR for CRC. The increased MMP-9 levels in the early postoperative period may be due to the acute inflammatory response, including increases in IL-1 and TNF mediated activation of neutrophils and macrophages. However, the spike during weeks 2-3 may be related to wound healing given MMP-9’s role in angiogenesis. This persistent elevation for 3 weeks after surgery may also enhance angiogenesis in residual cancer deposits postoperatively. Further studies are needed. Citation Format: Chandana S. K. Herath Mudiyanselage, Anuj R. Sharma, Neil Mitra, Aashutosh Sah, Xiaohong Yan, Pablo Palacios, Vesna Cekic, Richard L. Whelan. Plasma levels of Matrix metalloproteinases 9, an angiogenic promoting protein, are persistently elevated three weeks after minimally invasive colorectal resection (MICR) for cancer which may support residual tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5392.

TNFα induces matrix metalloproteinase-9 expression in monocytic cells through ACSL1/JNK/ERK/NF-kB signaling pathways

Studies have established the association between increased plasma levels of matrix metalloproteinase (MMP)-9 and adipose tissue inflammation. Tumor necrosis factor α (TNFα) was elevated in obesity and is involved in the induction of MMP-9 in monocytic cells. However, the underlying molecular mechanism was incompletely understood. As per our recent report, TNFα mediates inflammatory responses through long-chain acyl-CoA synthetase 1 (ACSL1). Therefore, we further investigated the role of ACSL1 in TNFα-mediated MMP-9 secretion in monocytic cells. THP-1 cells and primary monocytes were used to study MMP-9 expression. mRNA and protein levels of MMP-9 were determined by qRT-PCR and ELISA, respectively. Signaling pathways were studied using Western blotting, inhibitors, and NF-kB/AP1 reporter cells. We found that THP-1 cells and primary human monocytes displayed increased MMP-9 mRNA expression and protein secretion after incubation with TNFα. ACSL1 inhibition using triacsin C significantly reduced the expression of MMP-9 in the THP-1 cells. However, the inhibition of β-oxidation and ceramide biosynthesis did not affect the TNFα-induced MMP-9 production. Using small interfering RNA-mediated ACSL1 knockdown, we further confirmed that TNFα-induced MMP-9 expression/secretion was significantly reduced in ACSL1-deficient cells. TNFα-mediated MMP-9 expression was also significantly reduced by the inhibition of ERK1/ERK2, JNK, and NF-kB. We further observed that TNFα induced phosphorylation of SAPK/JNK (p54/46), ERK1/2 (p44/42 MAPK), and NF-kB p65. ACSL1 inhibition reduced the TNFα-mediated phosphorylation of SAPK/JNK, c-Jun, ERK1/2, and NF-kB. In addition, increased NF-κB/AP-1 activity was inhibited in triacsin C treated cells. Altogether, our findings suggest that ACSL1/JNK/ERK/NF-kB axis plays an important role in the regulation of MMP-9 induced by TNFα in monocytic THP-1 cells.

PORTO-001 study: Changes in the oral microbiome and matrix metalloproteinases in patients with oropharyngeal squamous cell carcinoma undergoing definitive chemoradiotherapy.

e18034 Background: Head and neck cancer patients treated with concurrent chemoradiotherapy (CRT) develop oral mucositis, with varying severity. However, knowledge about risk factors, biomarkers, treatment, and prognosis of oral mucositis is still limited. Methods: We designed an exploratory study to examine the changes in the oral microbiome and salivary and plasma levels of matrix metalloproteinases (MMP) in patients with locoregionally advanced oropharyngeal squamous cell carcinoma (OPSCC) undergoing definitive CRT. Patients were followed from screening to week 7 of treatment with CRT, which consisted of 70 Gy/35 fractions of radiation with cisplatin given at 100 mg/m2 q3weeks or weekly 40 mg/m2. Clinical and demographic data were collected at specified timepoints. Samples were collected at screening and on week 4 of treatment with CRT. A tumor swab was collected for microbiome analysis. Blood and saliva samples were collected for measurements of 7 MMPs and 26 other cytokines. The study population was summarized descriptively. The change in the cytokines and the α-diversity of microbiome data (week 4 vs screening) were examined using Wilcoxon signed rank test. Results: A total of 11 patients were included. Nine (82%) were male. 5 patients (45%) were stage III, and there were 2 patients (18%) for each of stages I, II, and IV. A history of smoking was present in 5 (45.4%) patients. p16 was positive in 9 (81.8%) patients. There was a median weight loss of 7.0% (5.1 kg) between screening and week 7 visits. Almost half (45%) of patients developed grade 2 oral mucositis. All patients developed radiation dermatitis, with most cases ranging between grades 2 and 3. There were no statistically significant changes in the salivary levels of cytokines. However, 1 patient developed clinical oral mucositis before all the other patients, at week 1, and this was associated with an upsurge in the salivary levels of IFN-γ, IL-6, TNF-α, MMP-1, MMP-2 and MMP-7. For all patients, there were statistically significant changes (median (95% confidence interval)) in the blood plasma levels of IP-10 (-0.1 fluorescence intensity (FI) (-0.3, -0.04), p = 0.01), MIP-1ß (0.2 FI (0.07, 0.5), p = 0.02), SDF-1α (1.4 pg/ml (0.07, 3.7), p = 0.02), MMP-1 (-0.4 pg/ml (-0.5, -0.09), p = 0.01), MMP-3 (0.4 pg/ml (0.03, 0.5), p = 0.02), and MMP-8 (-0.2 FI (-0.3, -0.02), p = 0.04). There was a 29.1% ((-3.0%, -32.8%), p = 0.005) reduction in α-diversity of microbiome at week 4 from screening. Conclusions: In this small series of patients diagnosed with OPSCC, there was a change in the plasma levels of IP-10, MIP-1ß, SDF-1α, MMP-1, MMP-3, and MMP-8, as well as a reduction in the α-diversity of the oral microbiome. Larger studies are needed to confirm these results. If confirmed, these changes might imply a potential role as predictive or pharmacodynamic biomarkers for oral mucositis.

Effect of eucalyptol on matrix metalloproteinase-9 and its tissue inhibitor in hypertensive rats.

Effects of eucalyptol, a key component of eucalyptus globules, on matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor (TIMP-1), compared with lisinopril, were investigated in a model of hypertension induced by chronic intraperitoneal (IP) injection of low dose nicotine in rats. The hypertensive rats were randomly allocated to 4 groups (n=8): Positive control (PC, untreated), eucalyptol-treated group (1.0 mg/kg, IP), lisinopril-treated group (10 mg/kg, IP), and eucalyptol+lisinopril-treated group. Systolic blood pressure and plasma levels of MMP-9 and TIMP-1 were measured. All treatments decreased the elevated blood pressure and plasma levels of MMP-9 and TIMP-1 most significantly with the combination group which showed non-significant differences from the normal control group. Lisinopril reduced plasma levels of MMP-9 and TIMP-1 more significantly than eucalyptol. In conclusion, eucalyptol significantly decreased the increased plasma levels of MMP-9 and TIMP-1 in nicotine-induced hypertension in rats. Moreover, its combination with lisinopril exerted more significant effects compared to each drug alone. This makes this combination particularly useful in hypertension and related cardiovascular disorders where suppression of MMP-9 and TIMP-1 activities decreases the related complications and improves the overall morbidity and mortality. To our knowledge, the current data are novel, and may open the way for development of a co-delivery system of both drugs which could be beneficial in treatment of hypertension in chronic smokers.

Plasma Levels of MMPs and TIMP-1 in Patients with Osteoarthritis After Recovery from COVID-19.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPS) play a key role in the pathogenesis of osteoarthritis (OA). Recent research showed the involvement of some MMPs in COVID-19, but the results are limited and contradictory. In this study, we investigated the levels of MMPs (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10) and TIMP-1 in the plasma of patients with OA after recovery from COVID- 19. The experiment involved patients aged 39 to 80 diagnosed with knee OA. All study participants were divided into three research groups: the control group included healthy individuals, the group OA included patients with enrolled cases of OA, and the third group of OA and COVID-19 included patients with OA who recovered from COVID-19 6-9 months ago. The levels of MMPs and TIMP-1 were measured in plasma by enzyme-linked immunosorbent assay. The study showed a change in the levels of MMPs in patients with OA who had COVID- 19 and those who did not have a history of SARS-CoV-2 infection. Particularly, patients with OA who were infected with coronavirus established an increase in MMP-2, MMP-3, MMP-8, and MMP-9, compared to healthy controls. Compared to normal subjects, a significant decrease in MMP-10 and TIMP-1 was established in both groups of patients with OA and convalescent COVID-19. Thus, the results suggest that COVID-19 can affect the proteolysis-antiproteolysis system even after a long postinfectious state and may cause complications of existing musculoskeletal pathologies.

Plasma Levels of Matrix Metalloproteinases 2 and 9 in Patients with Chronic Chagas Heart Disease and Systemic Arterial Hypertension: Correlation with TGF-Beta Plasma Levels.

Chronic Chagas heart disease (CCHD) and systemic arterial hypertension (SAH) frequently coexists in areas where Chagas disease is endemic. The effects of the association of both conditions (CCHD-SAH) on the extracellular matrix (ECM) remodeling are unknown. Matrix metalloproteinases (MMP) 2 and 9 are involved in ECM remodeling. The aim of this study was to evaluate MMP 2 and MMP9 in CCHD-SAH patients and to correlate their levels with those of the profibrogenic cytokine TGF-beta. We included 19 patients with CCHD-SAH, 14 patients with CCHD alone, and 19 controls matched by sex and age. MMP-2 and MMP-9 plasma levels were studied by gel zymography and showed as optical densities (OD). TGF-beta plasma levels were measured by double-ligand ELISA and expressed as pg/mL. Median (5th, 95th) MMP-2 plasma levels were 1224.7 OD (1160, 1433.5) in patients with CCHD alone, 1424.1 OD (1267.5, 1561) in patients with CCHD-SAH, and 940 OD (898.1, 1000.8) in controls (p=0.001). MMP-9 plasma levels were 1870 OD (1740, 1904.1) in patients with CCHD alone, 1754.6 OD (1650, 2049) in those with CCHD-SAH and 89.7 OD (80, 96) in controls (p=0.0003). MMP-9 plasma levels were higher than those of MMP 2 in patients with CCHD-SAH (p=0.01). No correlation was found between TGF-beta plasma levels with MMP-2 serum levels (r = 0.12; p=0.7), but a moderate negative correlation (r = -0.46; p=0.048) was observed between TGF-beta and MMP-9 plasma levels. MMP-2 and especially MMP-9 may play a role in the ECM remodeling process in patients with CCHD-SAH. TGF-Beta may counteract the MMP effect on the ECM remodeling process in patients with CCHD-SAH.

MMP-9 plasma level as biomarker of cochlear implantation outcome in cohort study of deaf children

PurposeIf before cochlear implantation it was possible to assay biomarkers of neuroplasticity, we might be able to identify those children with congenital deafness who, later on, were at risk of poor speech and language rehabilitation outcomes.MethodsA group of 40 children aged up to 2 years with DFNB1-related congenital deafness was observed in this prospective cohort study over three follow-up intervals (0, 8, and 18 months) after cochlear implant (CI) activation. Children were assessed for auditory development using the LittlEARS Questionnaire (LEAQ) score, and at the same time, measurements were made of matrix metalloproteinase-9 (MMP-9) plasma levels.ResultsThere were significant negative correlations between plasma levels of MMP-9 at 8-month follow-up and LEAQ score at cochlear implantation (p = 0.04) and LEAQ score at 18-month follow-up (p = 0.02) and between MMP-9 plasma levels at 18-month follow-up and LEAQ score at cochlear implantation (p = 0.04). As already reported, we confirmed a significant negative correlation between MMP-9 plasma level at cochlear implantation and LEAQ score at 18-month follow-up (p = 0.005). Based on this latter correlation, two clusters of good and poor CI performers could be isolated.ConclusionsThe study shows that children born deaf who have an MMP-9 plasma level of less than 150 ng/ml at cochlear implantation have a good chance of attaining a high LEAQ score after 18 months of speech and language rehabilitation. This indicates that MMP-9 plasma level at cochlear implantation is a good prognostic marker for CI outcome.

Longitudinal Changes in BDNF and MMP-9 Protein Plasma Levels in Children after Cochlear Implantation.

Congenitally deaf children who undergo cochlear implantation before 1 year of age develop their auditory skills faster than children who are implanted later. In this longitudinal study, a cohort of 59 implanted children were divided into two subgroups according to their ages at implantation-below or above 1 year old-and the plasma levels of matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and pro-BDNF were measured at 0, 8, and 18 months after cochlear implant activation, while auditory development was simultaneously evaluated using the LittlEARs Questionnaire (LEAQ). A control group consisted of 49 age-matched healthy children. We identified statistically higher BDNF levels at 0 months and at the 18-month follow-ups in the younger subgroup compared to the older one and lower LEAQ scores at 0 months in the younger subgroup. Between the subgroups, there were significant differences in the changes in BDNF levels from 0 to 8 months and in LEAQ scores from 0 to 18 months. The MMP-9 levels significantly decreased from 0 to 18 months and from 0 to 8 months in both subgroups and from 8 to 18 months only in the older one. For all measured protein concentrations, significant differences were identified between the older study subgroup and the age-matched control group.

Sex differences in Alzheimer’s disease: plasma MMP-9 and markers of disease severity

BackgroundStudies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored.MethodsOur sample included 238 amyloid-β (Aβ)-positive participants with MCI or AD dementia from the Alzheimer’s Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aβ42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data.ResultsTotal and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (β = 0.06 [−0.11 to −0.01], p = 0.031). Sex modified the association of CSF t-tau with total (β = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (β = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (β = −14.98 [−27.37 to −2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aβ42 among men (β = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (β = −2.10 [−3.97 to −0.27], p = 0.027 and β = −2.24 [−4.32 to −0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (β = 12.34 [3.02 to 21.65], p = 0.011) in women (β = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (β = 8.98 [0.27 to 17.68], p = 0.042).ConclusionsMMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women’s elevated susceptibility to AD.

Contribution of blood-brain barrier-related blood-borne factors for Alzheimer’s disease vs. vascular dementia diagnosis: A pilot study

BackgroundAlzheimer’s disease (AD) and vascular dementia (VaD) are the two most common types of neurodegenerative dementia among the elderly with similar symptoms of cognitive decline and overlapping neuropsychological profiles. Biological markers to distinguish patients with VaD from AD would be very useful. We aimed to investigate the expression of blood-brain barrier (BBB)-related blood-borne factors of soluble low-density lipoprotein receptor-related protein 1 (sLRP1), cyclophilin A (CyPA), and matrix metalloproteinase 9 (MMP9) and its correlation with cognitive function between patients with AD and VaD.Materials and methodsPlasma levels of sLRP1, CyPA, and MMP9 were analyzed in 26 patients with AD, 27 patients with VaD, and 27 normal controls (NCs). Spearman’s rank correlation analysis was used to explore the relationships among biomarker levels, cognitive function, and imaging references. Receiver operating characteristic (ROC) curve analysis was used to discriminate the diagnosis of AD and VaD.ResultsAmong these BBB-related factors, plasma CyPA levels in the VaD group were significantly higher than that in the AD group (p < 0.05). Plasma sLRP1 levels presented an increasing trend in VaD while maintaining slightly low levels in patients with AD (p > 0.05). Plasma MMP9 in different diagnostic groups displayed the following trend: VaD group > AD group > NC group, but the difference was not statistically significant (p > 0.05). Furthermore, plasma sLRP1 levels were positively related to MoCA scores, and plasma CyPA levels were significantly correlated with MTA scores (p < 0.05) in the AD group. Plasma MMP9 levels were negatively correlated with MoCA scores (p < 0.05) in the VaD groups. No significant correlation was detected between the other factors and different cognitive scores (p > 0.05). ROC analysis showed a good preference of plasma CyPA [AUC = 0.725, 95% CI (0.586–0.865); p = 0.0064] in diagnosis.ConclusionThe plasma CyPA level is a reference index when distinguishing between an AD and subcortical ischemic vascular dementia (SIVD) diagnosis. Blood-derived factors associated with the BBB may provide new insights into the differential diagnosis of neurodegenerative dementia and warrant further investigation.

Therapeutic effects of allopurinol on the function of left ventricular and activity of matrix metalloproteinase enzymes (MMPs) in patients with chronic heart failure.

Heart failure is a growing public health problem, especially in the elderly, often occurring due to ischemia and coronary artery disease. Allopurinol can protect against myocardial ischemia and improve myocardial energy utilization during ischemia. On the other hand, matrix metalloproteinase (MMP) enzymes play an essential role in causing atherosclerosis, obstruction, and myocardial infarction. Therefore, in the present study, the effect of allopurinol on the function of the left ventricular and the activity of MMP-1, MMP-2, MMP-3, and MMP-9 were evaluated in heart failure patients. In this clinical trial, 82 patients were randomly assigned to allopurinol or placebo in addition to standard treatment. Echocardiographic evaluations were performed before treatment and six months after treatment. Also, after allopurinol treatment, plasma and peripheral blood mononuclear cells were extracted from control and intervention groups. The active form of MMPs was measured by ELISA and mRNA expression by Real-time PCR. The rate of change in left ventricular ejection fraction in the allopurinol group was significantly higher than patients in the control group. There was also found more improvement in NYHA class in patients receiving allopurinol than in the control group. ELISA results showed that all plasma MMP levels in the control group were significantly higher than those in the allopurinol group (P<0.001). Quantitative determination of mRNA expression in MMPs by Real-time RT-PCR revealed that, except for MMP-9, there was no significant difference in the expression of evaluated MMPs between the treatment and control groups. In general, the results showed that long-term administration of allopurinol improves left ventricular function, and it has beneficial effects on the life quality of patients with heart failure.

Abstract P237: Matrix Metalloproteinases (MMPs) And Risk Of Incident Hemorrhagic And Ischemic Stroke: The Atherosclerosis Risk In Communities Study (ARIC)

Introduction: Matrix metalloproteinases (MMPs), belong to a family of zinc-dependent endopeptidases, have been found to induce stroke through its role in extracellular matrix destruction. MMPs also affect the stroke prognosis by disrupting blood brain barrier during stroke. Genetic association studies suggest that MMPs are involved in the pathogenesis of both ischemic and hemorrhagic stroke. Hypothesis: High MMP-2, MMP-9 and ratio of MMP-9/TIMP-1 are associated with higher risk of ischemic and hemorrhagic stroke. Method: After exclusion of missing data and prevalent stroke, 11,393 ARIC participants were followed from midlife (visit 3; 1993-1995) and 4,924 participants followed from late life (visit 5; 2011-2013) to 2019. Plasma levels of MMPs were measured by SOMAscan version 4 assay. Stroke cases were reviewed and adjudicated by neurologists. We used Cox models to examine the relationship between MMPs and stroke risk. Result: Mean age of participants were 60±5.7 at visit 3 and 76±5.2 at visit 5. At visit 3 55% were female and 21% Black. A total of 1,013 ischemic and 127 hemorrhagic strokes occurred over 22.34 years of follow-up for the visit 3 analysis and 319 ischemic and 30 hemorrhagic strokes over 7.24 years for the visit 5 analysis. A significant and positive association was detected for MMP-2 at visit 3 baseline for hemorrhagic stroke (HR (95% CI): 2.28 (1.14-4.57)) and at visit 5 baseline with ischemic stroke (1.65 (1.08-2.53)), after covariate adjustment. No associations were observed with MMP-9 and TIMP-1. Conclusion: Results of MMP-2 indicate a possible relationship with MMPs and stroke subtypes, but were not consistent. Though no significance were found for MMP-9 and TIMP-1, their direction of associations with stroke was consistent with the hypothesis.

Up-regulated lncRNA-PVT1 expression in peripheral blood mononuclear cells of patients with coronary artery disease is correlated with decreased interleukin-10 production.

Plasmacytoma variant translocation 1 (PVT1) is a newly discovered long non-coding RNA, which has not been previously studied in the inflammatory responses of the peripheral blood mononuclear cells (PBMCs) of patients with coronary artery disease (CAD). This cross-sectional study was conducted on 15 CAD patients and 15 non-CAD (NCAD) individuals. The PVT1 expression was assessed in the PBMCs of the participants using a real-time polymerase chain reaction. Interleukin (IL)-10, IL-22, and matrix metalloproteinase-9 (MMP-9) were measured in the plasma and supernatant of cultured PBMCs in the presence or absence of lipopolysaccharide (LPS) using flow cytometry and enzyme-linked immunosorbent assay. An increased expression of PVT1 was observed in the untreated PBMCs of CAD patients, compared to the NCAD group. The PVT1 was significantly up-regulated after LPS treatment in the PBMCs of both groups. Plasma MMP-9 levels were found to be higher in CAD patients than in the control individuals. The level of IL-10 and IL-22 production by the non-treated PBMCs of CAD cases was significantly lower than the NCAD group. Overall, in the examined population, PVT1 expression was negatively correlated with IL-10 secretion. Moreover, the results showed a significant negative correlation between PVT1 expression and IL-10 production by untreated cells. The PVT1 expression augmented in the PBMCs of CAD patients, which could be associated with the decreased IL-10 generation by the PBMCs of these patients.

Plasmatic MMP9 released from tumor-infiltrating neutrophils is predictive for bevacizumab efficacy in glioblastoma patients: an AVAglio ancillary study

We previously identified matrix metalloproteinase 2 (MMP2) and MMP9 plasma levels as candidate biomarkers of bevacizumab activity in patients with recurrent glioblastoma. The aim of this study was to assess the predictive value of MMP2 and MMP9 in a randomized phase III trial in patients with newly diagnosed glioblastoma and to explore their tumor source. In this post hoc analysis of the AVAglio trial (AVAGlio/NCT00943826), plasma samples from 577 patients (bevacizumab, n = 283; placebo, n = 294) were analyzed for plasma MMP9 and MMP2 levels by enzyme-linked immunosorbent assay. A prospective local cohort of 38 patients with newly diagnosed glioblastoma was developed for analysis of tumor characteristics by magnetic resonance imaging and measurement of plasma and tumor levels of MMP9 and MMP2. In this AVAglio study, MMP9, but not MMP2, was correlated with bevacizumab efficacy. Patients with low MMP9 derived a significant 5.2-month overall survival (OS) benefit with bevacizumab (HR 0.51, 95% CI 0.34–0.76, p = 0.0009; median 13.6 vs. 18.8 months). In multivariate analysis, a significant interaction was seen between treatment and MMP9 (p = 0.03) for OS. In the local cohort, we showed that preoperative MMP9 plasma levels decreased after tumor resection and were correlated with tumor levels of MMP9 mRNA (p = 0.03). However, plasma MMP9 was not correlated with tumor size, invasive pattern, or angiogenesis. Using immunohistochemistry, we showed that MMP9 was expressed by inflammatory cells but not by tumor cells. After cell sorting, we showed that MMP9 was expressed by CD45+ immune cells. Finally, using flow cytometry, we showed that MMP9 was expressed by tumor-infiltrating neutrophils. In conclusion, circulating MMP9 is predictive of bevacizumab efficacy and is released by tumor-infiltrating neutrophils.

Plasma matrix metalloproteinase 2 is associated with severity and mortality in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a life‐threatening disease characterized by vasoconstriction and remodeling of the pulmonary vessels. Risk stratification in PAH could potentially be improved by including novel biomarkers related to PAH pathobiology. We aimed to investigate the relationship between extracellular matrix (ECM)‐related proteins, survival, and European Society of Cardiology and European Respiratory Society (ESC/ERS) risk stratification scores in patients with PAH. Plasma samples and hemodynamics were collected from PAH patients during right heart catheterizations at diagnosis (n = 48) and early follow‐up, after treatment initiation (n = 33). Plasma levels of 14 ECM‐related proteins, with altered levels in PAH compared to healthy controls, were analyzed with proximity extension assays, and related to hemodynamics, transplant‐free survival time, and ESC/ERS risk score. Glypican‐1 levels were higher before versus after treatment initiation (p = 0.048). PAH patients with high plasma levels of matrix metalloproteinase (MMP) ‐2, MMP‐7, MMP‐9, MMP‐12, perlecan, and tissue inhibitor of metalloproteinase 4 (TIMP‐4) at baseline, had worse transplant‐free survival (p < 0.03) than patients with low levels. Hazard ratio (95% confidence interval) was for MMP‐2 1.126 (1.011–1.255), perlecan 1.0099 (1.0004–1.0196), and TIMP‐4 1.037 (1.003–1.071) in age and sex‐adjusted Cox‐regression model. MMP‐2 correlated with ESC/ERS risk scores (r s = 0.34, p = 0.019), mean right atrial pressure (r s = 0.44, p = 0.002), NT‐proBNP (r s = 0.49, p ≤ 0.001), and six‐minute walking distance (r s = −0.34, p = 0.02). The present study indicates that high levels of MMP‐2, perlecan, and TIMP‐4 are associated with poor survival in PAH. High plasma MMP‐2, correlated with poor prognosis in PAH. Further validation in larger studies is needed to better determine this association.

Influence plasma levels of matrix metalloproteinase among patients obese with or without metabolic syndrome

The association of metabolic syndrome (MS) with endothelial dysfunction could influence the synthesis and activity of matrix metalloproteinases (MMPs) which are a variety of endopeptidases, synthesized in several tissues. The present study was proposed to examine the matrix MMPs, tissue inhibitors of metalloproteinases (TIMPs) and Tumor Necrosis Factor α (TNF-α) in patients non-obese and obese with or without MS. We also investigate the possible association of these circulating levels with cardiovascular risk factors. The study has included 262 patients subdividing according to body mass index (BMI) and metabolic syndrome. MS was defined according to the NCEP–ATPIII report. Plasma MMP-1-2-9, TIMP-1-2, and TNF-α levels were determined using ELISA. In our study, the level of MMPs and TIMPs were higher in obese and MS patients. In obese patients, positive association were present between MMP-1 and body mass index (BMI) (r = 0.714, P = 0.071) and between TIMP-1 and systolic blood pressure (SBP) (r = 0.691, P = 0.058). In MS patients, MMP-3 and TIMP-1 were positively associated with waist circumference (WC) (r = 0.502, P = 0.020; r = 0.698, P = 0.001; respectively). MMP-1 and TNF-α were positively correlated with diastolic blood pressure (DBP) (r = 0.632, P = 0.006; r = 0.471, P = 0.049; respectively). In patients obese with MS, MMP-1 and MMP-2 were positively associated with BMI (r = 0.196, P = 0.034; r = 0.138, P = 0.081; respectively). Positive correlation were present between MMP-1 with SBP (r = 0.131, P = 0.06) and DBP (r = 0.173, P = 0.027). Also, MMP-2 was positively associated with Triglycerides in MS patients (r = 0.479, P = 0.018) and in patients obese with MS (r = 0.209, P = 0.007). MMP-3 and fasting plasma glucose were positively correlated in MS patients (r = 0.632, P = 0.002). These findings suggest that MMPs may have a role in the increased cardiovascular risk of patients obese with or without MS.