TNC Levels Research Articles

α9β1 integrin & its ligands as new potential biomarkers in FMF.

Background & objectives Familial Mediterranean Fever (FMF) manifests as a hereditary condition characterized by repeated bouts of fever, abdominal, chest, and joint discomfort, and swelling. Colchicine is the most common form of treatment, but it does not eliminate the disease. The underlying causes of the inflammatory mechanism are still not fully known. Methods A total of 20 healthy controls, 16 individuals with FMF in the attack period, and 14 in the remission period participated in the study. ITGA9, ITGB1, OPN, TNC, VEGF, VCAM-1, TGM2, TSP-1, Emilin-1, and vWF levels were measured by ELISA by obtaining serum from blood samples of individuals. In addition, gene expressions of α9β1 (ITGA9, ITGB1) and its best known ligands (TNC, SPP1) were analyzed by quantitative real-time PCR (qPCR). Results The findings of this study showed that serum levels of α9β1 and its ligands were higher in individuals with FMF in the attack period than in the healthy controls and the FMF group in the remission period (P<0.05). The marker levels of the healthy group were also higher than those in the remission period (p<0.05). In addition, when the gene expressions were compared between the healthy controls and FMF group, no significant difference was found for ITGA9, ITGB1, TNC, and SPP1 genes. Interpretation & conclusions The function of α9β1 and its ligands in FMF disease was investigated for the first time in this study as per our knowledge. Serum levels of these biomarkers may help identify potential new targets for FMF disease diagnosis and treatment approaches.

Regional levels of tenascin- C in patients with heart failure and atrial fibrillation

Abstract Background Tenascin-C (TNC) is an extracellular matrix glycoprotein that is upregulated at high levels during active tissue remodeling. The serum concentration of TNC has been reported to be increased in patients with several cardiac diseases. The aim of this study was 1) to measure the TNC plasma level in heart failure (HF) and atrial fibrillation (AF) patients compared to patients without structural heart disease and 2) to search for a local production in the heart. Methods This study included 13 patients with HF who underwent CRT- implantation (CRT- group), 13 patients with persistent AF who underwent left atrial catheter ablation (AF- group) and 13 patients without structural heart disease or AF, who underwent electrophysiological study (Control- group). Blood was collected at the beginning of the procedures from the coronary sinus (CS), superior vena cava (SVC) and aorta (Ao). Level of TNC-B (ng/dl) in the CS (TNC-CS), SVC (TNC-SVC) and aorta (TNC-Ao) was measured. Results Patients characteristics: CRT- group: mean age 74y, 8 male, LV- EF 32%, 3 with a history of atrial fibrillation. AF- group: mean age 68y, 9 male, LV- EF 55%. Control- group: mean age 54y, 9 male, LV- EF 65%. The TNC level in the SVC was in the CRT group significant elevated (6125 ± 2030 ng/ml vs 475 ± 238 ng/ml in controls (p&amp;lt;0.01). In the AF group the TNC level in the SVC as well was significantly higher 4983 ± 1814 ng/ml vs 475 ± 238 ng/ml in controls (p&amp;lt;0.01). The TNC level of the CRT- and the AF- group were not significant different (p= 0.219) (Figure 1). No significant differences were noted at the various collection sites (CS, SVC and aorta) between the 3 groups (p = 0.38). Discussion The TNC serum levels in HF- and AF- patients are elevated compared to a control group without structural heart disease and without a history of AF. We could not determinate, the source of serum TNC, differences in the level of TNC between CS and SVC and aorta were not visible. Whether an effective treatment of HF and AF will lower TNC levels and slow the disease progression needs to be evaluated in further studies.

Abstract 13166: Proteomic Pathways Across Ejection Fraction Categories in Heart Failure: An Exscel Substudy

Background: Ejection fraction (EF) is a key component of heart failure (HF) categorization, including the newly-proposed HF with mildly reduced EF (HFmrEF) category. The biologic basis of HFmrEF, as an entity distinct from HF with preserved EF (HFpEF) and reduced EF (HFrEF), has not been substantiated. Methods: The EXSCEL trial randomized participants with type 2 diabetes to once-weekly exenatide (EQW) vs. placebo. In participants with prevalent HF, we profiled ~5000 serum proteins. Principal component analysis (PCA) and ANOVA (FDR p&lt;0.1) were used to determine differences in factors and individual proteins between three EF groups, as documented in EXSCEL (EF&gt;55% [HFpEF], EF 40-55% [HFmrEF], EF&lt;40% [HFrEF]). Cox proportional hazards was used to assess relationships between baseline proteins and changes in protein level with incident HF hospitalization. Results: Of 1199 EXSCEL participants with prevalent HF, 284 (24%), 704 (59%) and 211 (18%) had HFpEF, HFmrEF and HFrEF, respectively. Eight PCA protein factors and 221 individual proteins within these factors differed significantly across the 3 groups. Levels of the majority of proteins (83.3%) demonstrated concordance between HFmrEF and HFpEF, but higher levels in HFrEF, including the domain of extracellular matrix, e.g. COL28A1, tenascin C [TNC]; p&lt;0.0001. A minority of proteins (1%) were concordant between HFmrEF and HFrEF including matrix metalloproteinase-9 (p&lt;0.0001). Baseline levels of 94% of the 221 significant proteins were associated with incident HF including domains of extracellular matrix (COL28A1, TNC), angiogenesis (ANG2, VEGFa, VEGFd), myocyte stretch (NTpro-BNP), and renal function (cystatin-C). Change in levels of 18 of these proteins from baseline to 12 months (including increase in TNC) predicted subsequent HF (p&lt;0.05). TNC levels were reduced by EQW compared with placebo (p&lt;0.0001). Conclusions: In this large clinical trial, we found that most proteins were similar between HFmrEF and HFpEF. A key ECM protein, tenascin C, showed this relationship, and baseline level and change in tenascin C predicted HF and changed beneficially with EQW. These results suggest that HFmrEF is more biologically similar to HFpEF and highlight prognostic and modifiable biomarkers that vary by EF.

Relationships Between Circulating Tenascin-C Levels and Gonadal Hormones in Male Patients with Depressive Disorder: A Retrospective, Cross-Sectional Study.

Tenascin-C (TNC) is an extracellular matrix glycoprotein closely associated with the progression of psychiatric disorders. The present study was performed to investigate the possible association between serum gonadal hormones and TNC levels in male patients with depressive disorder. We measured serum TNC levels by enzyme-linked immunosorbent assay. In addition, we investigated the influence of testosterone (T) and estradiol (E2) on TNC levels in primary neuronal cultures. Patients with depression had lower levels of T, free tri-iodothyronine (FT3), thyroid-stimulating hormone (TSH), and the T/E2 ratio than healthy control patients. Levels of TNC and high-sensitivity C-reactive protein were significantly higher in patients than in healthy volunteers. Serum TNC concentrations were negatively associated with levels of E2 and T and with the T/E2 ratio. Levels of TNC, TSH, and FT3 and the T/E2 ratio were predictors of depression. Among men with depression, TNC was negatively associated with T levels and with the T/E2 ratio. Incubating pheochromocytoma 12 cells with the combination of T and E2 greatly decreased TNC levels in the culture medium. Increased TNC levels may predict imbalance between T and E2 in patients with depression, and gonadal hormones may modulate TNC expression in vivo.

Tenascin C Has a Modest Protective Effect on Acute Lung Pathology during Methicillin-Resistant Staphylococcus aureus-Induced Pneumonia in Mice.

ABSTRACTTenascin C (TNC) is an extracellular matrix protein with immunomodulatory properties that plays a major role during tissue injury and repair. TNC levels are increased in patients with pneumonia and pneumosepsis, and they are associated with worse outcomes. Methicillin-resistant Staphylococcus aureus (MRSA) is a Gram-positive bacterium that is a major causative pathogen in nosocomial pneumonia and a rising cause of community-acquired pneumonia. To study the role of TNC during MRSA-induced pneumonia, TNC sufficient (TNC+/+) and TNC-deficient (TNC−/−) mice were infected with MRSA via the airways and euthanized after 6, 24, and 48 h for analysis. Pulmonary transcription of TNC peaked at 6 h, while immunohistochemistry revealed higher protein levels at later time points. Although TNC deficiency was not associated with changes in bacterial clearance, TNC−/− mice showed increased levels of TNF-α and IL-6 in bronchoalveolar lavage fluid during the acute phase of infection when compared with TNC+/+ mice. In addition, TNC−/− mice showed more severe pulmonary pathology at 6, but not at 24 or 48 h, after infection. Together, these data suggest that TNC plays a moderate protective role against tissue pathology during the acute inflammatory phase, but not during the bacterial clearance phase, of MRSA-induced pneumonia. These results argue against an important role of TNC on disease outcome during MRSA-induced pneumonia.IMPORTANCE Recently, the immunomodulatory properties of TNC have drawn substantial interest. However, to date most studies made use of sterile models of inflammation. In this study, we examine the pathobiology of MRSA-induced pneumonia in a model of TNC-sufficient and TNC-deficient mice. We have studied the immune response and tissue pathology both during the initial insult and also during the resolution phase. We demonstrate that MRSA-induced pneumonia upregulates pulmonary TNC expression at the mRNA and protein levels. However, the immunomodulatory role of TNC during bacterial pneumonia is distinct from models of sterile inflammation, indicating that the function of TNC is context dependent. Contrary to previous descriptions of TNC as a proinflammatory mediator, TNC-deficient mice seem to suffer from enhanced tissue pathology during the acute phase of infection. Nonetheless, besides its role during the acute phase response, TNC does not seem to play a major role in disease outcome during MRSA-induced pneumonia.

Seasonal nonstructural carbohydrate patterns in dewberry (Rubus spp.) roots

AbstractApplying control measures when carbohydrate levels are low can decrease the likelihood of plant survival, but little is known about the carbohydrate cycles of dewberry (Rubus spp.), a problematic weed group on cranberry (Vaccinium macrocarpon Aiton) farms. Weedy Rubus plants were collected from areas adjacent to production beds on commercial cranberry farms in Massachusetts, two locations per year for 2 yr. For each site and year, four entire plants were collected at five phenological stages: budbreak, full leaf expansion, flowering, fruit maturity, and after onset of dormancy. Root sections were analyzed for total nonstructural carbohydrates (TNC; starch, sucrose, fructose, and glucose). Overall trends for all sites and years showed TNC were lowest at full leaf expansion or flowering; when sampled at dormancy, TNC concentrations were greater than or equal to those measured at budbreak. Starch, a carbohydrate form associated with long-term storage, had low levels at budbreak, leaf expansion, and/or flowering with a significant increase at fruit maturity and the onset of dormancy, ending at levels higher than those found at budbreak. The concentration of soluble sugars, carbohydrate forms readily usable by plants, was highest at budbreak compared with the other four phenological samplings. Overall, our findings supported the hypothesis that TNC levels within the roots of weedy Rubus plants can be predicted based on different phenological growth stages in Massachusetts. However, recommendations for timing management practices cannot be based on TNC cycles alone; other factors such as temporal proximity to dormancy may also impact Rubus plants recovery, and further research is warranted. Late-season damage should allow less time for plants to replenish carbohydrate reserves (before the onset of dormancy), thereby likely enhancing the effectiveness of weed management tactics over time. Future studies should consider tracking the relationship between environmental conditions, phenological stages, and carbohydrate trends.

First trimester placental mesenchymal stem cells improve cardiac function of rat after myocardial infarction via enhanced neovascularization

Acute myocardial infarction (AMI) is the most critical heart disease. Mesenchymal stem cells (MSCs) have been widely used as a therapy for AMI for several years. The human placenta has emerged as a valuable source of transplantable cells of mesenchymal origin that can be used for multiple cytotherapeutic purposes. However, the different abilities of first trimester placental chorion mesenchymal stem cells (FCMSCs) and third trimester placental chorion mesenchymal stem cells (TCMSCs) have not yet been explored. In this study, we aimed to compare the effectiveness of FCMSCs and TCMSCs on the treatment of AMI. FCMSCs and TCMSCs were isolated and characterized, and then they were subjected to in vitro endothelial cell (EC) differentiation induction and tube formation to evaluate angiogenic ability. Moreover, the in vivo effects of FCMSCs and TCMSCs on cardiac improvement were also evaluated in a rat MI model. Both FCSMCs and TCMSCs expressed a series of MSCs surface markers. After differentiation induction, FCMSCs-derived EC (FCMSCs-EC) exhibited morphology that was more similar to that of ECs and had higher CD31 and vWF levels than TCMSCs-EC. Furthermore, tube formation could be achieved by FCMSCs-EC that was significantly better than that of TCMSCs-EC. Especially, FCMSCs-EC expressed higher levels of pro-angiogenesis genes, PDGFD, VEGFA, and TNC, and lower levels of anti-angiogenesis genes, SPRY1 and ANGPTL1. In addition, cardiac improvement, indicated by left ventricular end-diastolic diameter (LVEDd), left ventricular end-systolic diameter (LVEDs), left ventricular ejection fraction (LVEF) and left ventricular shortening fraction (LVSF), could be observed following treatment with FCMSCs, and it was superior to that of TCMSCs and Bone marrow MSCs (BMSCs). FCMSCs exhibited a superior ability to generate EC differentiation, as evidenced by in vitro morphology, angiogenic potential and in vivo cardiac function improvement; further, increased levels of expression of pro-angiogenesis genes may be the mechanism by which this effect occurred.

The Future of Autonomous Vehicles: Lessons from the Literature on Technology Adoption

AbstractThe introduction and adoption of autonomous vehicles (AVs) will likely reshape the transportation system and many economic activities. The economic literature on technology adoption, based on studies in agriculture and other sectors, provides lessons on the diffusion of AVs and its social and economic impacts. We rely on the threshold model of diffusion, where heterogeneous agents make decisions pursuing their self‐interests. Applications of the threshold model point to case studies of other technologies where one can gain information and make predictions about the future of AVs. We find that private ownership of AVs may prevail after a transition period, as was the case in other technologies like computers, tractors, and conventional vehicles. With technological progress, the cost of privately owning AVs may decline. Further, there will be an increase in vehicle miles traveled (VMT) per capita, there may be more vehicles on the road, and perhaps the transportation user‐base will expand to include those currently facing limited mobility. Congestion is likely to depend on the tradeoff between the expansion of VMT and increased efficiency of AVs to communicate and help regulate traffic. Furthermore, differentiation of vehicles will increase as driving time becomes freed for other activities. These trends may lead to increased greenhouse gas emissions and expansion of the transportation sector. Finally, the technology will evolve and may result in complementary innovations needing to be addressed, including the “last 10 feet” problem. It is evident that the future of the transportation system governed by AVs is most likely not going to be sustainable. This necessitates the importance of developing and enforcing rigorous policies at the metropolitan level and TNC levels to ensure a sustainable evolution of the future of transportation mobility.

Tenascin-C accelerates adverse ventricular remodelling after myocardial infarction by modulating macrophage polarization.

Tenascin-C (TN-C) is an extracellular matrix protein undetected in the normal adult heart, but expressed in several heart diseases associated with inflammation. We previously reported that serum TN-C levels of myocardial infarction (MI) patients were elevated during the acute stage, and that patients with high peak TN-C levels were at high risk of left ventricular (LV) remodelling and poor outcome, suggesting that TN-C could play a significant role in the progression of ventricular remodelling. However, the detailed molecular mechanisms associated with this process remain unknown. We aimed to elucidate the role and underlying mechanisms associated with TN-C in adverse remodelling after MI. MI was induced by permanent ligation of the coronary artery of TN-C knockout (TN-C-KO) and wild type (WT) mice. In WT mice, TN-C was expressed at the borders between intact and necrotic areas, with a peak at 3 days post-MI and observed in the immediate vicinity of infiltrating macrophages. TN-C-KO mice were protected from ventricular adverse remodelling as evidenced by a higher LV ejection fraction as compared with WT mice (19.0 ± 6.3% vs. 10.6 ± 4.4%; P < 0.001) at 3 months post-MI. During the acute phase, flow-cytometric analyses showed a decrease in F4/80+CD206lowCD45+ M1 macrophages and an increase in F4/80+CD206highCD45+ M2 macrophages in the TN-C-KO heart. To clarify the role of TN-C on macrophage polarization, we examined the direct effect of TN-C on bone marrow-derived macrophages in culture, observing that TN-C promoted macrophage shifting into an M1 phenotype via Toll-like receptor 4 (TLR4). Under M2-skewing conditions, TN-C suppressed the expression of interferon regulatory factor 4, a key transcription factor that controls M2-macrophage polarization, via TLR4, thereby inhibiting M2 polarization. These results suggested that TN-C accelerates LV remodelling after MI, at least in part, by modulating M1/M2-macrophage polarization.

The effect of recovery from heat stress on circulating bioenergetics and inflammatory biomarkers.

Heat stress (HS) jeopardizes animal productivity and health. The intestinal barrier is sensitive to HS and heat-induced hyperpermeability plays a key role in its pathophysiology. However, the biology of recovery following HS is less understood. Thus, study objectives were to determine the temporal pattern of metabolic, inflammatory, and intestinal histological parameters during HS recovery. Female pigs (n = 32; 19.5 ± 0.5 kg BW) were sacrificed following exposure to 1 of 4 environmental treatments: 1) constant thermoneutral (TN) conditions (TNC; 24.2 ± 0.5°C), 2) no TN recovery post HS (0D), 3) 3 d of TN recovery post HS (3D), and 4) 7 d of TN recovery post HS (7D). The HS protocol was cyclical (33.6 ± 1.8 to 37.4 ± 2.1°C) and lasted for 3 d for all HS treatments. During the 3 d of HS, rectal temperature, skin temperature, and respiration rates were increased (1.3°C, 4.8°C, and 77 breaths/min, respectively; P < 0.01) and ADFI was decreased (27%; P < 0.01) compared to TNC pigs. Skin temperature tended to be decreased 0.6°C in 3D pigs during days 1-3 of recovery (P = 0.06) and was decreased 1.6 and 0.7°C during days 1-3 and 4-7 of recovery, respectively, in 7D pigs (P ≤ 0.03) compared to TNC. Relative to TNC pigs, ADFI remained 14% decreased during days 1-3 of recovery in both 3D and 7D pigs, and 17% decreased during days 4-7 in 7D pigs (P ≤ 0.01). Plasma glucose was decreased (10%; P = 0.03) for 0D and 3D relative to TNC pigs. Circulating lipopolysaccharide-binding protein was increased in 3D and 7D vs. TNC pigs (110 and 147%, respectively; P = 0.01) and tended to increase linearly with increasing recovery time (P = 0.08). Circulating tumor necrosis factor alpha was decreased (15%) in 0D pigs and increased linearly with advancing recovery time (P < 0.01). Jejunum and ileum villus height were reduced 17 and 11% in 0D vs. TNC pigs and increased linearly with progressive recovery time (P < 0.01). Jejunum and ileum mucosal surface areas were reduced 17 and 9% in 0D pigs and remained decreased in the jejunum while the ileum recovered to TNC levels by day 3 of recovery. Relative to TNC pigs, goblet cell area was similar in jejunum and colon of 0D pigs but was reduced in the ileum of 0D pigs and in jejunum, ileum, and colon of 3D and 7D relative to TNC pigs (P < 0.01). In summary, HS has deleterious effects on intestinal morphology that seem to improve with recovery time. In contrast, feed consumption remained suppressed and inflammatory biomarkers indicative of leaky gut increased following the heat load.

Interleukin 1 Receptor-Like 1 Protein (ST2) is a Potential Biomarker for Cardiomyopathy in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a rare, fatal X-linked disorder characterized by the lack of dystrophin, a key sarcolemma muscle protein.Cardiac failure is a significant cause of death in DMD subjects. The purpose of our research was to identify potential cardiac serum biomarkers associated with DMD cardiomyopathy. This is an observational, case-controlled study using subjects from the CINRG DMD natural history study with cardiomyopathy (ejection fraction (EF) <55%; shortening fraction (SF) <28%), subjects without cardiomyopathy (EF≥55%; SF≥28%) compared to normal healthy volunteer subjects. The DMD with cardiomyopathy group had significantly lower average EF and SF (EF=45±10/SF=25±2%) than the DMD without cardiomyopathy group (EF=58±5% and SF=32±3%; p<0.01). Among a selected set of potential biomarkers for cardiomyopathy (MMP9, BNP, GAL3, CRP, LEP, TNC, TLR4 and ST2) we validated ST2 as significantly elevated in the serum of DMD cardiomyopathy group (35,798±4884pg/mL) compared to normal controls (9940±2680pg/mL; p<0.01; n=6). Matrix metallopeptidase 9 (MMP9) levels were found significantly increased in both DMD groups compared to controls (p<0.01). No significant differences were seen in BNP, GAL3, CRP, LEP, TNC or TLR4 levels. Increased ST2 levels were found in serum of DMD subjects compared to healthy volunteers and further elevated in DMD subjects with cardiomyopathy. Future studies correlating cardiomyopathy with ST2 levels may allow for improved non-invasive monitoring of cardiac disease in DMD subjects.

Tenogenic Differentiation of Human Embryonic Stem Cells.

Tendon healing is complex to manage because of the limited regeneration capacity of tendon tissue; stem cell-based tissue engineering approaches may provide alternative healing strategies. We sought to determine whether human embryonic stem cells (hESC) could be induced to differentiate into tendon-like cells by the addition of exogenous bone morphogenetic protein (BMP)12 (growth differentiation factor[GDF]7) and BMP13 (GDF6). hESC (SHEF-1) were maintained with or without BMP12/13 supplementation, or supplemented with BMP12/13 and the Smad signaling cascade blocking agent, dorsomorphin. Primary rat tenocytes were included as a positive control in immunocytochemistry analysis. A tenocyte-like elongated morphology was observed in hESC after 40-days continuous supplementation with BMP12/13 and ascorbic acid (AA). These cells displayed a tenomodulin expression pattern and morphology consistent with that of the primary tenocyte control. Analysis of tendon-linked gene transcription in BMP12/13 supplemented hESC demonstrated consistent expression of COL1A2, COL3A1, DCN, TNC, THBS4, and TNMD levels. Conversely, when hESCs were cultured in the presence of BMP12/13 and dorsomorphin COL3A1, DCN, and TNC gene expression and tendon matrix formation were inhibited. Taken together, we have demonstrated that hESCs are responsive to tenogenic induction via BMP12/13 in the presence of AA. The directed in vitro generation of tenocytes from pluripotent stem cells may facilitate the development of novel repair approaches for this difficult to heal tissue.

Value of serum tenascin-C in patients with acute myocardial infarction

BackgroundMyocardial infarction (MI) is defined as myocardial cell necrosis due to significant and sustained ischemia. TN-C is an extracellular matrix glycoprotein that is expressed in several important steps during the very early stage of cardiogenesis. TN-C is not normally expressed in the adult heart, but transiently appears during pathological conditions and plays important roles in tissue remodeling. AimTo study the role of TN-C in myocardial infarction patients and to evaluate its role as a predictor of HF in these patients. MethodsThis study was conducted on 45 cases uniformly divided into 3 closely matched (in age and sex) groups as follows: Group (I) includes 15 patients who were suffering from AMI; Group (II) includes 15 patients who were suffering from HF on top of MI; and Group (III) includes 15 healthy volunteers coming for regular annual checkup. 3–6ml venous blood was collected on the day of admission under complete aseptic conditions and stored at −70°C until assayed by ELISA. ResultsTN-C levels in the sera of patients with AMI Group (I) were significantly higher than those of healthy volunteers. Moreover, in Group I of AMI, a positive correlation between TN-C level on one side and CK, CK-MB and troponin T level on the other side was found. TN-C levels in the sera of patients with congestive heart failure on top of acute MI Group (II) were significantly higher than those of healthy volunteers. Pro-BNP levels in patients with heart failure Group (II) were significantly higher than those with AMI not complicated with heart failure Group (I). Levels of pro-BNP were also positively correlated with those of TN-C in patients with heart failure on top of AMI Group (II). ConclusionsSerum TN-C might be a novel marker reflecting active structural remodeling in the myocardium following infarction, with high TN-C levels at acute stages possibly predicting progression of LV remodeling. Also, the incorporation of a combination of serum TN-C and plasma BNP levels may improve risk stratification for congestive heart failure after AMI. Further studies on large scale are needed for more evaluation of TN-C role in HF.

Matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, B+ tenascin-C and ED-A+ fibronectin in dilated cardiomyopathy: Potential impact on disease progression and patients' prognosis

BackgroundDilated cardiomyopathy (DCM) is associated with heart failure and increased mortality and there is no reliable biomarker to estimate patients' prognosis. During cardiac remodeling, an extensive reorganization of the extracellular matrix occurs. The study was aimed to investigate matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1) and fetal tenascin-C (B+ Tn-C) and fibronectin (ED-A+ Fn) variants known to be involved in that process. Methods and resultsIn 187 patients with DCM, levels of MMP-9, TIMP-1 and B+ Tn-C in serum as well as B+ Tn-C and ED-A+ Fn in tissue were quantified and subjected to univariate analysis. For all serum markers, concentrations above a calculated threshold were associated with decreased survival (MMP-9: p=0.008, TIMP-1: p=0.001, B+ Tn-C: p<0.001) and a significantly higher risk to die or undergo transplantation. In tissue, a reexpression of B+ Tn-C and ED-A+ Fn could be shown. Protein deposition levels of ≥4.5% for B+ Tn-C and ≥2.1% for ED-A+ Fn were associated with a significantly decreased survival (p=0.001 for B+ Tn-C, p=0.031 for ED-A+ Fn) and an increased risk to die or undergo transplantation. In a multivariate analysis, TIMP-1 is the superior parameter to predict transplantation free survival (p=0.027). ConclusionsSerum levels of MMP-9, TIMP-1 and B+ Tn-C and tissue levels of B+ Tn-C and ED-A+ Fn are promising markers for risk assessment. The reoccurrence of ED-A+ Fn and the availability of a human antibody usable as a vehicle for targeted drug delivery might be the basis for novel therapeutic strategies.

Type A dissection and chronic dilatation: tenascin-C as a key factor in destabilization of the aortic wall

Tenascin-C plays an important role in myocardial and vascular remodelling. We hypothesized that tenascin-C is a key factor in the development of degenerative disease of the ascending aorta, leading to chronic dilatation and acute aortic dissection. Ascending aortic wall specimens were obtained during surgery for chronic dilatation (n=52) and acute Type A dissection (n=30). Patients (n=12) undergoing aortic valve replacement served as controls. Tenascin-C expression was evaluated by immunostaining and semi-quantitatively assessed using the ImageJ software. TN-C levels in peripheral blood were determined by enzyme-linked immunosorbent assay. Histological examination showed a clear difference between chronic dilatation and acute dissection. In chronic dilatation, tenascin-C staining was homogenously distributed throughout the media parallel to vascular smooth muscle cells. In acute dissection, a strong staining with a heterogenous and spotty distribution was detected. Control aortas showed no tenascin-C staining. Tenascin-C expression was significantly higher in Type-A dissection compared with chronic dilatation. This was accompanied by a significant elevation of tenascin-C levels in peripheral blood in acute dissection. There was no statistical correlation between the tenascin-C level in peripheral blood and the aortic diameter either in dissection or in dilatation. Tenascin-C is a marker of progressive destabilization of the aortic wall independent of size in chronic dilatation and acute dissection. Therefore, it might be a valuable tool in guiding intervention strategies in patients with disease of the ascending aorta.

Prognostic Value of Serum Tenascin-C Levels on Long-Term Outcome After Acute Myocardial Infarction

BackgroundTenascin-C (TN-C), an extracellular matrix glycoprotein, is not normally expressed in the adult heart but transiently reappears under various pathologic conditions to play important roles in tissue remodeling. It is unclear whether serum TN-C levels add prognostic information independent from traditional prognostic markers. Methods and ResultsWe assessed 239 patients with first ST-segment elevation myocardial infarction who underwent successful percutaneous coronary intervention. We measured serum TN-C and plasma B-type natriuretic peptide (BNP) levels on day 5 after admission and compared long-term clinical outcome. During the follow-up period (24.3 ± 13 months), 54 patients experienced primary composite cardiac events (cardiac death or hospitalization for worsening heart failure). Multivariable Cox proportional hazards analysis indicated that serum TN-C (hazard ratio 2.92, 95% confidence interval [CI] 1.55–5.67; P < .001) and plasma BNP levels (hazard ratio 1.84, 95% CI 1.17–2.97; P = .008) were significant independent predictors for cardiac events after adjustment for multiple confounders. The combination of TN-C and BNP resulted in an increase of the c-statistic from 0.821 to 0.877 (P < .001) and an integrated discrimination improvement gain of 14.0% (P < .001). ConclusionsSerum TN-C level on day 5 after admission is potentially useful for early risk stratification after AMI beyond established prognostic markers.

Tenascin-C induces inflammatory mediators and matrix degradation in osteoarthritic cartilage

BackgroundTenascin-C (TN-C) is an extracellular matrix glycoprotein that is involved in tissue injury and repair processes. We analyzed TN-C expression in normal and osteoarthritic (OA) human cartilage, and evaluated its capacity to induce inflammatory and catabolic mediators in chondrocytes in vitro. The effect of TN-C on proteoglycan loss from articular cartilage in culture was also assessed.MethodsTN-C in culture media, cartilage extracts, and synovial fluid of human and animal joints was quantified using a sandwich ELISA and/or analyzed by Western immunoblotting. mRNA expression of TN-C and aggrecanases were analyzed by Taqman assays. Human and bovine primary chondrocytes and/or explant culture systems were utilized to study TN-C induced inflammatory or catabolic mediators and proteoglycan loss. Total proteoglycan and aggrecanase -generated ARG-aggrecan fragments were quantified in human and rat synovial fluids by ELISA.ResultsTN-C protein and mRNA expression were significantly upregulated in OA cartilage with a concomitant elevation of TN-C levels in the synovial fluid of OA patients. IL-1 enhanced TN-C expression in articular cartilage. Addition of TN-C induced IL-6, PGE2, and nitrate release and upregulated ADAMTS4 mRNA in cultured primary human and bovine chondrocytes. TN-C treatment resulted in an increased loss of proteoglycan from cartilage explants in culture. A correlation was observed between TN-C and aggrecanase generated ARG-aggrecan fragment levels in the synovial fluid of human OA joints and in the lavage of rat joints that underwent surgical induction of OA.ConclusionsTN-C expression in the knee cartilage and TN-C levels measured in the synovial fluid are significantly enhanced in OA patients. Our findings suggest that the elevated levels of TN-C could induce inflammatory mediators and promote matrix degradation in OA joints.

B domain containing Tenascin-C: A new urine marker for surveillance of patients with urothelial carcinoma of the urinary bladder?

Background ECM remodelling during tumorigenesis entails the re-occurrence of different Tn-C L splicing variants. In patients with urothelial carcinoma of the urinary bladder (UBC), B and C domain containing Tenascin-C (B + and C + Tn-C) urine levels were shown to be increased in case of muscle invasiveness. Thus, the present study was aimed at examining the ability of B + and C + Tn-C as potential urinary surveillance markers of UBC patients. Methods Urine levels of B + and C + Tn-C were determined by ELISA in 35 UBC patients during a 2 year follow-up period after therapy and related to clinical diagnosis and histological stage in 4 defined groups representing typical courses of disease. Results B + Tn-C levels showed significant differences between cases of tumour progression or regression. The urine levels of B + Tn-C could be used to discriminate between cases without tumour recurrence and such with tumour existence (cut-off value: 0.8 ng/ml) or between non-muscle invasive and muscle invasive tumour growth (cut-off value: 3.5 ng/ml). Conclusions Progression of UBC with time is accompanied by significant changes in urinary levels of B + Tn-C. Urinary B + Tn-C can therefore be suggested as a valuable urine surveillance marker in UBC follow-up care.

Circulating tenascin-C levels in patients with dilated cardiomyopathy in the course of Emery-Dreifuss muscular dystrophy

BackgroundTenascin-C (TN-C), an extracellular matrix glycoprotein, is of diagnostic and prognostic value in different heart diseases. One such dilated cardiomyopathy (DCM) with conduction disturbances is one of the most serious manifestations in Emery-Dreifuss muscular dystrophy (EDMD). Herein we therefore detail work to evaluate the potential significance of circulating TN-C in patients with EDMD, speculating that it may define the cardiac dysfunction, especially in patients who may be cardiac asymptomatic, but still be at risk of sudden death. Material and methodSerum levels of TN-C were quantified by sandwich immunoassay ELISA in 25 EDMD patients (10 with laminopathy—AD-EDMD and 15 with emerinopathy—X-EDMD), 8 X-EDMD carriers, 9 disease controls (patients with dystrophinopathy), and 15 age-matched healthy controls. Fourteen of the EDMD patients had repeated TN-C examinations after 3 to 7years. ResultsThe levels of circulating TN-C were elevated in AD-EDMD and X-EDMD patients, as well as in some X-EDMD carriers, and patients with dystrophinopathy. The correlation between the TN-C level and left end-systolic ventricle diameter (LVDD) was significant in X-EDMD, while those with left atrium diameter (LAD) and the ejection fraction (EF) were not. In “follow-up” studies TN-C levels were not found to change over time in AD-EDMD, while rising in X-EDMD. ConclusionsThe presented results indicate that assessments of circulating TN-C levels may help to identify EDMD patients at risk of dilated cardiomyopathy. TN-C might therefore be considered a candidate for a new biomarker, useful in detecting of cardiomyopathy and in further monitoring of the DCM therapy in patients with EDMD.

High circulating levels of large splice variants of tenascin-C is associated with mortality and cardiovascular disease in chronic kidney disease patients

ObjectivesTenascin-C (TN-C) is an adhesion-modulating extracellular matrix glycoprotein which is overexpressed in various organs under disease conditions (infection and inflammation). In patients with heart disease, plasma TN-C levels have been shown to be predictive of cardiac remodeling. Chronic kidney disease (CKD) is associated with a state of chronic inflammation and high cardiovascular morbidity and mortality. MethodsIn a prospective observational study, we examined the relationship between plasma concentration of large splice variants of TN-C (cTN-C) and cardiovascular outcomes, we studied a cohort of 94 prevalent CKD patients (mean±SD age: 68±13; 31% at CKD stages 2–3, 31% at stages 4–5, 38% at stage 5D). ResultsPlasma cTN-C levels were elevated in this population and tended to rise as CKD progressed, with the increase becoming statistically significant at CKD stage 4–5 and 5D. Multivariate linear regression analysis indicated that CKD stage (p=0.04), IL-6 (p=0.02) and albumin (p=0.02) were independently associated with plasma cTN-C levels. During follow-up (mean duration: 969±405 days), 32 patients died (19 from CV events, 7 from infectious diseases and 6 from other causes). In a crude analysis, higher plasma cTN-C levels predicted overall and CV mortality (p=0.007 and p=0.003, respectively) and were associated with higher occurrence of CV events. Cox analyses confirmed that elevated plasma cTN-C levels were independently associated with cardiovascular events, cardiovascular and overall mortality. ConclusionOur findings suggest, for the first time, that plasma cTN-C levels are independently associated with cardiovascular outcomes in CKD patients. Further studies are needed in order to confirm the above observations and better understand TN-C's role in cardiovascular remodeling in CKD.