A study of inflammatory biomarkers in crystalline silica exposed rock drillers.

BACKGROUND: Crystalline silica (CS) exposure can cause serious lung disease in humans, but mechanisms of pulmonary toxicity have not been completely elucidated. AIMS: To assess pro-inflammatory and anti-inflammatory biomarkers and biomarkers related to the development of chronic obstructive pulmonary disease and fibrosis in serum of rock drillers exposed to CS. METHODS: Rock drillers (N = 123) exposed to CS and non-specified particulate matter (PM) were compared to 48 referents without current or past exposure to PM in a cross-sectional study. RESULTS: The rock drillers had been exposed to CS for 10.7 years on average. Geometric mean (GM) current exposure was estimated to 36 µg/m3. Their GM concentration of matrix metalloproteinase 12 (MMP-12) was significantly higher (16 vs. 13 ng/L; p = 0.04), while interleukin (IL) 6 and IL-8 were significantly lower compared to the referents. Also pentraxin 3 was significantly lower (3558 vs. 4592 ng/L; p = 0.01) in the rock drillers. A dose-response relationship was observed between cumulative exposure to CS and MMP-12, the highest exposed subgroup having significantly higher MMP-12 concentrations than the referents. CONCLUSION: Exposure to CS may increase circulating MMP-12 concentrations in a dose-response related fashion. The results may also suggest a down-regulation of pro-inflammatory pathways.

Circulating MMP-12 as Potential Biomarker in Evaluating Disease Severity and Efficacy of Sublingual Immunotherapy in Allergic Rhinitis.

Background: Allergic rhinitis (AR) is a highly heterogeneous disease, and allergen-specific immunotherapy (AIT) is an effective treatment. This study aims to evaluate the circulating mas-related G protein-coupled receptor-X2 (MRGPRX2) and matrix metalloproteinase-12 (MMP-12) levels in evaluating disease severity and predicting efficacy of SLIT in AR patients. Methods: We enrolled 110 moderate-severe persist AR patients (AR group) and 40 healthy controls (HC group). Circulating levels of MRGPRX2 and MMP-12 were measured, and their associations with disease severity were evaluated. All AR patients were assigned to receive sublingual immunotherapy (SLIT), and the efficacy was evaluated, and serum samples were collected at 1 year and 3 years after treatment. The correlations between serum MRGPRX2 and MMP-12 and clinical efficacy were assessed. Results: The serum concentrations of MRGPRX2 and MMP-12 were significantly higher in the AR group than the HC group, and the elevated MMP-12 levels were correlated with VAS and TNSS, and serum MRGPRX2 levels were correlated with VAS. Finally, 100 and 80 patients completed 1-year and 3-year follow-up and were classified into effective and ineffective groups. Serum MRGPRX2 and MMP-12 levels were lower in the effective group than the ineffective group. Although serum MRGPRX2 and MMP-12 levels did not significantly change after 1 year SLIT, serum MMP-12 levels were decreased 3 years post-SLIT than baseline and 1 year post-SLIT levels. Receiver operating characteristic (ROC) showed that serum MMP-12 was a potential biomarker for predicting the efficacy of SLIT. Conclusion: Serum MRGPRX2 and MMP-12 appeared to be promising biological indicators in reflecting disease severity in AR patients. Moreover, circulating MMP-12 might serve as a reliable predictor for clinical responsiveness of SLIT.

Causal Effect of MMP-1 (Matrix Metalloproteinase-1), MMP-8, and MMP-12 Levels on Ischemic Stroke: A Mendelian Randomization Study.

Background and Purpose: MMP (matrix metalloproteinase) levels have been widely associated with ischemic stroke risk and poststroke outcome. However, their role as a risk factor or as a subeffect because of ischemia is uncertain. Methods: We performed a literature search of genome-wide studies that evaluate serum/plasma levels of MMPs. We used a 2-sample Mendelian randomization approach to evaluate the causality of MMP levels on ischemic stroke risk or poststroke outcome, using 2 cohorts: MEGASTROKE (n=440 328) and GODs (n=1791). Results: Genome-wide association studies of MMP-1, MMP-8, and MMP-12 plasma/serum levels were evaluated. A significant association, which was also robust in the sensitivity analysis, was found with all ischemic strokes: MMP-12 (odds ratio=0.90 [95% CI, 0.86­0.94]; q value=7.43×10−5), and with subtypes of stroke, large-artery atherosclerosis: MMP-1 (odds ratio=0.95 [95% CI, 0.92­0.98]; q value=0.01) and MMP-12 (odds ratio=0.71 [95% CI, 0.65­0.77]; q value=5.11×10−14); small-vessel occlusion: MMP-8 (odds ratio=1.24 [95% CI, 1.06­1.45]; q value=0.03). No associations were found in relation to stroke outcome. Conclusions: Our study suggests a causal link between lower serum levels of MMP-12 and the risk of ischemic stroke, lower serum levels of MMP-1 and MMP-12 and the risk of large-artery stroke and higher serum levels of MMP-8 and the risk of lacunar stroke.

Plasma Protein Profile of Carotid Artery Atherosclerosis and Atherosclerotic Outcomes: Meta-Analyses and Mendelian Randomization Analyses.

[Figure: see text].

Imbalanced MMP-3 and MMP-12 serum levels in systemic lupus erythematosus patients with Jaccoud's arthropathy and a distinctive MRI pattern.

OBJECTIVE: Metalloproteinase (MMP)-3 and MMP-12 are proteolytic enzymes especially implicated in joint inflammation. This study aims to evaluate their association with arthritis features and hand MRI abnormalities in patients with SLE. METHODS: Fifty SLE patients, with a mean (s.d.) age of 48.1 (14.6) years were tested for MMP-3 and MMP-12 serum levels, then further classified according to the presence of X-ray erosions and joint deformities. Eighteen RA patients aged 47.9 (11.8) and 14 healthy people aged 46.0 (11.0) were enrolled as control groups. A subgroup of 28 SLE patients underwent a dominant-hand MRI; the detected changes were classified and semi-quantitatively scored as capsular swelling, synovitis, edematous or proliferative tenosynovitis, bone oedema, bone erosions. Statistical analysis was performed using multiple regression models. RESULTS: MMP-3 were significantly higher in patients with Jaccoud's arthropathy (JA) (22.1 ng/ml, P < 0.05) and independently associated with hsCRP serum levels (B-coeff 0.50; r = 0.30; P < 0.05). MMP-12 serum levels were significantly lower in patients with JA (0.18 ng/ml, P < 0.05) and inversely associated with the prednisone daily dose (B-coeff -0.03; r = -0.44; P < 0.01). Capsular swelling and edematous tenosynovitis, the most prevalent hand MRI changes in patients with JA, associated with higher MMP-3 (B-coeff 0.12; r = 0.66; P < 0.01 and B-coeff 0.08; r = 0.59; P < 0.01, respectively) and lower MMP-12 serum levels (B-coeff -7.4; r = -0.50; P < 0.05 and B-coeff -5.2; r = -0.44; P = 0.05, respectively). CONCLUSION: Imbalanced MMP-3 and MMP-12 serum levels are influenced by inflammation and glucocorticoids in SLE patients and associated with JA and distinctive hand MRI changes.

Matrix metalloproteinase-12 cleaved fragment of titin as a predictor of functional capacity in patients with heart failure and preserved ejection fraction.

OBJECTIVES: Serum levels of matrix metalloproteinase-12 cleaved fragment of titin (TIM), a novel circulatory biomarker specific for cardiac titin degradation, has emerged as a potential biomarker in cardiovascular diseases. In this work, we aimed to evaluate the association between TIM and maximal functional capacity assessed by the percentage of predicted peak exercise oxygen uptake (pp-peakVO2) in patients with heart failure and preserved ejection fraction (HFpEF). Design. In this post-hoc study, we included 46 stable symptomatic (New York Heart Association II-III) HFpEF patients enrolled in the TRAINING-HF study (NCT02638961). pp-peak-VO2 was calculated from baseline values. Baseline circulating levels of TIM were measured by competitive ELISA in serum from the TRAINING-HF patients. The independent association between TIM and pp-peakVO2 was evaluated by multivariate linear regression analysis. Results. The mean age of the sample was 73.8 ± 8.7 years, 56.5% were females, and 76.1% were on NYHA II. The medians of pp-peakVO2 and TIM were 60.9% (50.4-69.3), and 130.1 ng/mL (98.1-159.5), respectively. The median of NT-proBNP was 912 pg/mL (302-1826). pp-peakVO2 was significant and inversely correlated with TIM (r= -41, p = .005). In multivariate analysis, after adjusting for NYHA class, hypertension, body mass index, and glomerular filtration rate, higher TIM was significantly associated with lower pp-peak VO2 (p = .029). Conclusions. In this sample of stable and symptomatic HFpEF patients, higher serum levels of TIM identified patients with worse functional status.

Shear Stress and Aortic Strain Associations With Biomarkers of Ascending Thoracic Aortic Aneurysm.

BACKGROUND: This study aims to investigate the association of wall shear stress (WSS) and aortic strain with circulating biomarkers including matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinase (TIMP), and exosomal level of microRNA (miRNA) in ascending aortic aneurysms of patients with bicuspid or tricuspid aortic valve. METHODS: A total of 76 variables from 125 patients with ascending aortic aneurysms were collected from (1) blood plasma to measure plasma levels of miRNAs and protein activity; (2) computational flow analysis to estimate peak systolic WSS and time-average WSS (TAWSS); and (3) imaging analysis of computed tomography angiography to determine aortic wall strain. Principal component analysis followed by logistic regression allowed the development of a predictive model of aortic surgery by combining biomechanical descriptors and biomarkers. RESULTS: The protein activity of MMP-1, TIMP-1, and MMP-2 was positively correlated to the systolic WSS and TAWSS observed in the proximal ascending aorta (eg, R = 0.52, P < .001, for MMP-1 with TAWSS) where local maxima of WSS were found. For bicuspid patients, aortic wall strain was associated with miR-26a (R = 0.55, P = .041) and miR-320a (R = 0.69, P < .001), which shows a significant difference between bicuspid and tricuspid patients. Receiver-operating characteristics curves revealed that the combination of WSS, MMP-1, TIMP-1, and MMP-12 is predictive of aortic surgery (area under the curve 0.898). CONCLUSIONS: Increased flow-based and structural descriptors of ascending aortic aneurysms are associated with high levels of circulating biomarkers, implicating adverse vascular remodeling in the dilated aorta by mechanotransduction. A combination of shear stress and circulating biomarkers has the potential to improve the decision-making process for ascending aortic aneurysms to a highly individualized level.

Severity of chronic obstructive pulmonary disease with 'exacerbator with emphysema phenotype' is associated with potential biomarkers.

OBJECTIVE: The present study was designed to investigate the biomarkers levels of fractalkine (FKN), neutrophil elastase (NE) and matrix metalloproteinase-12 (MMP-12) in chronic obstructive pulmonary disease (COPD) with 'exacerbator with emphysema phenotype' and to evaluate the associations between the biomarkers levels and the severity of disease by spirometric measurements. METHODS: A total of 84 COPD patients and 49 healthy controls were enrolled in our study. ELISA were utilised to detect the FKN, MMP-12 and NE in serum from all subjects. RESULTS: FKN (p<0.001), NE (p=0.039) and MMP-12 (p<0.001) in serum of COPD patients showed higher levels than that of healthy control subjects. Serum FKN (p<0.001), MMP-12 (p<0.001) and NE (p=0.043) levels were significantly higher in severe and very severe COPD patients than that in mild and moderate COPD patients. Circulating FKN, MMP-12 and NE expression levels were significantly elevated (p<0.001) in COPD smokers compared with COPD non-smokers. The smoke pack years were negatively correlated with FEV1%pred (r=-0.5036), FEV1/FVC ratio (r=-0.2847) (FEV, forced expiratory volume; FVC, forced vital capacity). Similarly, we observed a strong positive correlation between the smoke pack years and serum levels of FKN (r=0.4971), MMP-12 (r=0.4315) and NE (r=0.2754). FEV1%pred was strongly negatively correlated with cytokine levels of FKN (r=-0.4367), MMP-12 (r=-0.3295) and NE (r=-0.2684). Likewise, FEV1/FVC ratio was negatively correlated with mediators of inflammation levels of FKN (r=-0.3867), MMP-12 (r=-0.2941) and NE (r=-0.2153). CONCLUSION: Serum FKN, MMP-12 and NE concentrations in COPD patients are directly associated with the severity of COPD with 'exacerbator with emphysema phenotype'. This finding suggests that FKN, MMP-12 and NE might play an important role in the pathophysiology of COPD.

Increased levels of inflammatory biomarker CX3CL1 in patients with chronic obstructive pulmonary disease.

OBJECTIVE: To investigate the concentration of CX3CL1 in serum of patients with chronic obstructive pulmonary disease (COPD), and to evaluate the associations between the CX3CL1 level and systemic inflammation, small airway obstruction, and COPD assessment test (CAT) scores in COPD patients. METHODS: Enzyme-linked immunosorbent assay were utilized to detect the CX3CL1 protein in serum separately from 64 patients with COPD and 53 healthy controls. RESULTS: Compared with healthy non-smokers, healthy smokers and COPD non-smokers, serum CX3CL1 protein levels were significantly elevated in COPD smokers (258.33 ±â€¯56.27 pg/mL versus 177.32 ±â€¯43.21 pg/mL, 185.64 ±â€¯47.03 pg/mL, and 226.55 ±â€¯51.79 pg/mL, P < 0.05). Correlation analysis indicated that serum CX3CL1 in COPD smokers was negatively correlated with FEV1/FVC (justified r = -0.319, P < 0.001), FEV1/Pre (justified r = -0.476, P < 0.001), FEV3/FVC (justified r = -0.354, P < 0.001), MMEF25-75/Pre (justified r = -0.428, P < 0.001), but positively correlated with CRP (justified r = 0.331, P < 0.001) and MMP-12 (justified r = 0.352, P < 0.001). However, our results showed no significant correlation between serum CX3CL1 of COPD smokers and the diffusing capacity of the lung for carbon monoxide (DLCO) (justified r = 0.0397, P = 0.6025), but a positive correlation with COPD assessment test (CAT) scores (justified r = 0.367, P < 0.001). Finally, through multivariate linear analysis, statistical results demonstrated age (ß = -0.2694, P = 0.005), FEV1/Pred (ß = -0.2653, P = 0.003), CRP (ß = 0.1427, P = 0.0478) and MMP-12 (ß = 0.430, P < 0.001) are independent parameters associated with CX3CL1. CONCLUSION: The results demonstrated that elevated circulating CX3CL1 level is associated with the systemic inflammation, small airway obstruction, and CAT scores in COPD patients, suggesting that CX3CL1 may play crucial roles in the pathogenesis of COPD. Blocking CX3CL1 might prevent the progression of chronic obstructive pulmonary disease.

Inflammatory mediators in exhaled breath condensate and peripheral blood of healthy donors and stable COPD patients.

Objective: The aim of this work was to compare matrix metalloproteinase-9 and -12, tissue inhibitor of metalloproteinase-1 and -4, and neutrophil elastase in exhaled breath condensate (EBC) and peripheral blood of patients with COPD. Methods: Peripheral blood and EBC samples from COPD patients and healthy donors were collected. In serum and EBC, MMP-9, MMP-12, NE, TIMP-1, and TIMP-4 proteins were detected by ELISA. The mRNA expression levels of MMP-9, MMP-12, NE, TIMP-1, and TIMP-4 in peripheral blood mononuclear cells (PBMCs) were analyzed by qRT-PCR. Results: The protein levels of MMP-9 (p=.034) and MMP-12 (p=.041) in the EBC of COPD smokers were higher than those of COPD never-smokers. The concentrations of TIMP-1 (p=.072) and TIMP-4 (p=.084) in the EBC of COPD smokers were higher than those of COPD never-smokers; however, the difference was not statistically significant. MMP-9 (r=-0.78, p<.0001) and TIMP-1 (r=-0.71, p<.0001) levels in EBC were significantly negatively correlated with pulmonary function FEV1%pred. The protein levels of MMP-12 (r=-0.37, p=.034) and TIMP-4 (r=-0.34, p=.041) were also negatively correlated with FEV1%pred. The expression of MMP-9, MMP-12, NE, TIMP-1, and TIMP-4 in PBMCs and serum of COPD smokers were significantly higher than those of control never-smokers (p<.05). Conclusions: Exhaled MMP-9, MMP-12, TIMP-1, and TIMP-4 levels increased in stable COPD patients and were negatively correlated with FEV1%pred, which suggests the usefulness of their measurement in EBC for the monitoring of airway inflammation. However, to better assess their diagnostic or prognostic value, larger studies are necessary.

Matrix Metalloproteinases in COPD and atherosclerosis with emphasis on the effects of smoking.

BACKGROUND: Matrix metalloproteinases (MMP´s) are known biomarkers of atherosclerosis. MMP´s are also involved in the pathophysiological processes underlying chronic obstructive pulmonary disease (COPD). Cigarette smoking plays an important role in both disease states and is also known to affect the concentration and activity of MMP´s systemically. Unfortunately, the epidemiological data concerning the value of MMP´s as biomarkers of COPD and atherosclerosis with special regards to smoking habits are limited. METHODS: 450 middle-aged subjects with records of smoking habits and tobacco consumption were examined with comprehensive spirometry, carotid ultrasound examination and biomarker analysis of MMP-1, -3, -7, -10 and -12. Due to missing data 33 subjects were excluded. RESULTS: The remaining 417 participants were divided into 4 different groups. Group I (n = 157, no plaque and no COPD), group II (n = 136, plaque but no COPD), group III (n = 43, COPD but no plaque) and group IV (n = 81, plaque and COPD). Serum levels of MMP-1,-7,-10-12 were significantly influenced by smoking, and MMP-1, -3, -7 and-12 were elevated in subjects with COPD and carotid plaque. This remained statistically significant for MMP-1 and-12 after adjusting for traditional risk factors. CONCLUSION: COPD and concomitant plaque in the carotid artery were associated with elevated levels of MMP-1 and -MMP-12 even when adjusting for risk factors. Further studies are needed to elucidate if these two MMP´s could be useful as biomarkers in a clinical setting. Smoking was associated with increased serum levels of MMP´s (except for MMP-3) and should be taken into account when interpreting serum MMP results.

The role of MMP-12 gene polymorphism - 82 A-to-G (rs2276109) in immunopathology of COPD in polish patients: a case control study.

BACKGROUND: Major symptoms of chronic obstructive pulmonary disease (COPD) are chronic bronchitis and emphysema leading from lung tissue destruction, that is an effect of an imbalance between metalloproteinases (MMPs) and their tissue inhibitors activity. As potential factor involved in this COPD pathogenesis, MMP-12 is considered. We investigated the role of genetic polymorphism and protein level of MMP-12 in the COPD development among Poles. METHODS: We analyzed - 82 A > G SNP in the promoter region of MMP-12 gene (rs2276109) among 335 smoked COPD patients and 309 healthy individuals, including 110 smokers. Additionally, 60 COPD patients and 61 controls (23 smokers) were tested for serum levels of MMP-12 using ELISA. All subjects were analyzed for lung function using spirometry (FEV1% and FEV1/FVC parameters). RESULTS: We observed that -82G allele and -82GG homozygous genotype frequencies of the SNP rs2276109 were significantly lower in COPD patients than in controls (12.5% vs 16.9%, respectively; χ2 = 4.742, p = 0.02 for allele and 0.5% vs 3.9%, respectively; χ2 = 9.0331, p = 0.01 for genotype). Moreover, -82G allele was more frequent in controls smokers than in non-smokers (22.3% vs 14.1%, χ2 = 6.7588, p = 0.01). Serum level of MMP-12 was significantly higher in COPD patients than in controls groups (6.8 ng/ml vs 3.3 ng/ml, respectively; F = 7.433, p < 0.0001), although independently of analyzed gene polymorphisms. Additionally, no correlation between parameters of lung function (FEV1% and FEV1/FVC) and protein level was found. CONCLUSIONS: We found that -82G allele of SNP rs2276109 was associated with reduced risk of COPD, and COPD patients released more MMP-12 than healthy individuals, but independently on this SNP.

The association between serum metalloproteinase concentration, obesity, and hormone levels in reproductive-aged women.

INTRODUCTION: Increased levels and activity of some matrix metalloproteinases (MMPs) are described in obesity-related vascular diseases. Factors that influence MMP blood concentration are still being investigated. This research aims to evaluate the concentration of most types of MMPs: collagenases (MMP-1, -3, -8, -13), matrilysin (MMP-7), gelatinase (MMP-9), and metalloelastase (MMP-12) in serum of women in reproductive age in relation with their body mass index (BMI), age, oestradiol, and progesterone concentrations. MATERIAL AND METHODS: Blood samples were taken from 54 healthy reproductive-aged women with normal menstrual cycles. The weight and height of all women were measured, and body mass index (BMI) was calculated. Concentration of MMP-1, -3, -7, -8, -9, -12, and MMP-13 was evaluated using a Procarta Immunoassay Kit. Serum concentrations of oestradiol and progesterone were evaluated by immunochemiluminescence (32 in the proliferative and 20 in the secretory phase of menstrual cycle). The results of the study were statistically calculated using Pearson, Spearman, and Kruskal-Wallis tests. RESULTS: Positive correlation between MMP-7, -8, -9, -12, and -13 levels and BMI was demonstrated. Significantly higher concentrations of MMPs were found especially in obese women compared to women with normal BMI. In healthy, regularly menstruating premenopausal women, MMP levels did not correlate with oestradiol and progesterone concentrations. CONCLUSIONS: The results suggest that body mass can influence MMP serum concentration in women with regular menstrual cycles.

MMP-3 (-1171 5A/6A; Lys45Glu) variants affect serum levels of matrix metalloproteinase (MMP)-3 and correlate with severity of COPD: A study of MMP-3, MMP-7 and MMP-12 in a Tunisian population.

BACKGROUND: The present study aimed to examine the role of matrix metalloproteinase (MMP)-3 [(-1171) 5A/6A; Lys45Glu (A/G)], MMP-7 [(-181) A/G] and MMP-12 [(-82) A/G; Asn357Ser (A/G)] variants in the development and severity of chronic obstructive pulmonary disease (COPD) in Tunisians. METHODS: Plethysmography was performed in all participants to measure forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC parameters. Genotyping of MMP-3, MMP-7 and MMP-12 polymorphisms was carried out in 138 patients with COPD and 216 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism. Serum levels of MMPs and cytokines (interleukin-6, tumor necrosis factor-α) were determined by an enzyme-linked immunosorbent assay. RESULTS: No significant correlations were observed between genetic variations in MMP-3, MMP-7 and MMP-12 and the risk of development of COPD. Additionally, no impact of MMP-7 (-181) A/G and MMP-12 [(-82) A/G; Asn357Ser (A/G)] polymorphisms was observed on the respective protein levels and clinical parameters of the disease. Interestingly, both MMP-3 (-1171) 5A/6A and Lys45Glu (A/G) variants were associated with respiratory function, as well as with serum levels of MMP-3 in COPD patients. A relationship was found between the (-1171) 6A and 45Glu (G) alleles of the MMP-3 gene and enhanced airflow limitation among COPD patients. Additionally, carriers of the 6A6A and 45 GG genotypes present higher MMP-3 levels than noncarriers. CONCLUSIONS: MMP-3 (-1171) 5A/6A and Lys45Glu (A/G) polymorphisms were associated with the decline of lung function among COPD patients. These results could be linked to the upregulation of MMP-3 in serum from COPD patients carrying the (-1171) 6A and 45 G homozygous genotypes.

Biomarkers of oxidative stress and protein-protein interaction in chronic obstructive pulmonary disease.

CONTENT: The increased oxidative stress in chronic obstructive pulmonary disease (COPD) patients is the result of increased inhaled oxidants, generated by various cells of the airways. OBJECTIVE: The investigation included measurements of malondiadehyde (MDA), uric acid, ascorbic acid, and matrix metalloproteinase-12 (MMP-12) in COPD patient. We also performed genetic analysis for protein-protein interaction (PPI) network. MATERIALS AND METHODS: The study was conducted on healthy subjects with normal lung function (NS, 14 subjects) and 28 patients (Global Initiative for Chronic Obstructive Lung Disease (Gold) 1 and Gold 2) with COPD. RESULTS: There was significant (p < .001) increase in MMP-12, MDA and uric acid levels as compared to healthy controls. A significant (p < .001) decline in ascorbic acid level was observed in COPD patients. The PPI was found to be 0.833 which indicated that proteins present in COPD are linked. DISCUSSION AND CONCLUSION: This study suggests oxidative stress plays an important role in COPD and the PPI provide indication that proteins present in COPD are linked.

Expression of matrix metalloproteinases-12 in ST-segment elevation myocardial infarction: A case-control study.

Matrix metalloproteinases-12 (MMP12) can lead to degradation of elastin resulting in plaque destabilization and rupture. MMP12 also facilitates platelet aggregation, adhesion, and granule secretion. However, evidence in the literature related to the function of MMP12 in ST-segment elevation myocardial infarction (STEMI) is little. This study investigated the expression of MMP12 in human coronary thrombus and examined the relationship between plasma MMP12 and STEMI.Arterial plasma was obtained from 46 STEMI patients and 52 stable angina pectoris (SAP) patients and 30 controls with angiographically normal coronary arteries. Coronary thrombi were obtained from 26 STEMI patients with a large thrombus burden (LTB). The expression levels of MMP12 in coronary thrombus were analyzed by immunohistochemistry and immunofluorescence, reverse transcription-polymerase chain reaction (RT-PCR), Western blotting (WB) and casein zymography. In addition, MMP12 concentration measured by enzyme-linked immunosorbent assay (ELISA) and activity measured by fluorescence resonance energy transfer (FRET) were used to assess the levels in plasma.We confirmed the expression of MMP12 in human coronary thrombus. MMP12 was secreted mainly in active form of 45 kDa in coronary thrombus. In plasma samples of the STEMI group, MMP12 concentrations were found to be higher than the SAP group (5.030 ±â€Š2.24 pg/mL vs 3.010 ±â€Š1.99 pg/mL, P < .05) but with lower MMP12 activity (332 ±â€Š77 RFU vs 458 ±â€Š91 RFU, P < .05). Also, the STEMI group demonstrated much higher MMP12 concentrations than the normal coronary artery control group (5.030 ±â€Š2.24 pg/mL vs 1.720 ±â€Š0.51 pg/mL, P < .05) and with lower MMP12 activity (332 ±â€Š77 RFU vs 549 ±â€Š112 RFU, P < .05). In addition, the STEMI group had significantly higher tissue inhibitor of metalloproteinases-1 (TIMP1) concentration (573.40 ±â€Š270.60 pg/mL) than SAP group (384.50 ±â€Š147.70 pg/mL) and control group (219.90 ±â€Š154.80 pg/mL, P < .05). The imbalance in MMP12/TIMP ratio was observed in the STEMI group compared with SAP and control group (P < .05).This study demonstrated that MMP12 exists in human coronary thrombus. Patients with STEMI have elevated plasma level of MMP12 and the imbalance of MMP12/TIMP1. These data supported that MMP12 might be of potential relevance in STEMI.

Autoantibodies against aldehyde-modified collagen type IV are associated with risk of development of myocardial infarction.

BACKGROUND: Oxidation of LDL particles entrapped in the extracellular matrix of the arterial wall is a key factor in the development of atherosclerosis. Lipid oxidation products, such as malondialdehyde (MDA), react with surrounding extracellular matrix proteins and cause modifications that are recognized by the immune system. MDA modification of collagen type IV is increased in carotid lesions from symptomatic patients and correlates with autoantibodies against MDA-modified collagen type IV in plasma. OBJECTIVE: The aim of this study was to determine whether autoantibodies against MDA-modified collagen type IV predict risk of development of myocardial infarction (MI). METHODS: Plasma levels of MDA-modified collagen type IV IgM and IgG antibodies were analysed by enzyme-linked immunosorbent assay in 385 subjects with incident MI during 13 years of follow-up and 410 age- and sex-matched controls in the Malmö Diet and Cancer study. RESULTS: MDA-modified collagen type IV IgG levels were higher in cases with incident MI than in controls. Subjects in the highest tertile of MDA-modified collagen type IV IgG had an increased risk of MI (hazard ratio 1.56, 95% confidence interval 1.22-2.00, P for trend 0.0004). This association remained significant after adjusting for factors included in the Framingham risk score and diabetes. High levels of MDA-collagen type IV IgG were associated with increased carotid intima-media thickness and elevated plasma levels of matrix metalloproteinase 10 and 12. CONCLUSIONS: Immune responses against MDA-modified collagen type IV are associated with more severe carotid disease and increased risk of MI. These immune responses may reflect LDL oxidation in the artery wall, but could also affect the atherosclerotic disease process.

Integrative studies implicate matrix metalloproteinase-12 as a culprit gene for large-artery atherosclerotic stroke.

BACKGROUND: Ischaemic stroke and coronary heart disease are important contributors to the global disease burden and share atherosclerosis as the main underlying cause. Recent evidence from a genome-wide association study (GWAS) suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at chromosome 11q22.3 were associated with large-vessel ischaemic stroke. Here, we evaluated and extended these results by examining the relationship between MMP12 and atherosclerosis in clinical and experimental studies. METHODS AND RESULTS: Plasma concentrations of MMP12 were measured at baseline in 3394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD I array. The plasma MMP12 concentration showed association with incident cardiovascular and cerebrovascular events (130 and 67 events, respectively, over 36 months) and carotid intima-media thickness progression (P = 3.6 × 10-5 ). A GWAS of plasma MMP12 concentrations revealed that SNPs rs499459, rs613084 and rs1892971 at chr11q22.3 were independently associated with plasma MMP12 (P < 5 × 10-8 ). The lead SNPs showed associations with mRNA levels of MMP12 and adjacent MMPs in atherosclerotic plaques. MMP12 transcriptomic and proteomic levels were strongly significantly increased in carotid plaques compared with control arterial tissue and in plaques from symptomatic versus asymptomatic patients. By combining immunohistochemistry and proximity ligation assay, we demonstrated that MMP12 localizes to CD68 + macrophages and interacts with elastin in plaques. MMP12 silencing in human THP-1-derived macrophages resulted in reduced macrophage migration. CONCLUSIONS: Our study supports the notion that MMP12 is implicated in large-artery atherosclerotic stroke, functionally by enhancing elastin degradation and macrophage invasion in plaques.

Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) features multiorgan fibrosis orchestrated predominantly by activated myofibroblasts. Endothelial-to-mesenchymal transition (EndoMT) is a transdifferentiation by which endothelial cells (ECs) lose their specific morphology/markers and acquire myofibroblast-like features. Here, we determined the possible contribution of EndoMT to the pathogenesis of dermal fibrosis in SSc and two mouse models. METHODS: Skin sections were immunostained for endothelial CD31 or vascular endothelial (VE)-cadherin in combination with α-smooth muscle actin (α-SMA) myofibroblast marker. Dermal microvascular ECs (dMVECs) were prepared from SSc and healthy skin (SSc-dMVECs and H-dMVECs). H-dMVECs were treated with transforming growth factor-ß1 (TGFß1) or SSc and healthy sera. Endothelial/mesenchymal markers were assessed by real-time PCR, immunoblotting and immunofluorescence. Cell contractile phenotype was assayed by collagen gel contraction. RESULTS: Cells in intermediate stages of EndoMT were identified in dermal vessels of either patients with SSc or bleomycin-induced and urokinase-type plasminogen activator receptor (uPAR)-deficient mouse models. At variance with H-dMVECs, SSc-dMVECs exhibited a spindle-shaped appearance, co-expression of lower levels of CD31 and VE-cadherin with myofibroblast markers (α-SMA+ stress fibres, S100A4 and type I collagen), constitutive nuclear localisation of the EndoMT driver Snail1 and an ability to effectively contract collagen gels. Treatment of H-dMVECs either with SSc sera or TGFß1 resulted in the acquisition of a myofibroblast-like morphology and contractile phenotype and downregulation of endothelial markers in parallel with the induction of mesenchymal markers. Matrix metalloproteinase-12-dependent uPAR cleavage was implicated in the induction of EndoMT by SSc sera. CONCLUSIONS: In SSc, EndoMT may be a crucial event linking endothelial dysfunction and development of dermal fibrosis.