Higher Tenascin-C Levels Research Articles

The serum tenascin C level is a marker of metabolic disorder-related inflammation affecting pancreatic cancer prognosis

Obesity is a risk factor for pancreatic cancer development, partly due to the tissue environment of metabolic disorder-related inflammation. We aimed to detect a tissue environment marker triggered by obesity-related metabolic disorders related to pancreatic cancer progression. In murine experiments, Bl6/j mice fed a normal diet (ND) or a high-fat diet (HFD) were orthotopically injected with mPKC1, a murine-derived pancreatic cancer cell line. We used stocked sera from 140 pancreatic cancer patients for analysis and 14 colon polyp patients as a disease control. Compared with ND-fed mice, HFD-fed mice exhibited obesity, larger tumors, and worse prognoses. RNA sequencing of tumors identified tenascin C (TNC) as a candidate obesity-related serum tissue environment marker with elevated expression in tumors of HFD-fed mice. Serum TNC levels were greater in HFD-fed mice than in ND-fed mice. In pancreatic cancer patients, serum TNC levels were greater than those in controls. The TNC-high group had more metabolic disorders and greater CA19-9 levels than did the TNC-low group. There was no relationship between serum TNC levels and disease stage. Among 77 metastatic patients treated with chemotherapy, a high serum TNC concentration was an independent poor prognostic factor. Pancreatic cancer patients with high serum TNC levels experienced progression more rapidly.

Tenascin-C and Interleukin-17 Up-regulation in Axial Spondyloarthritis Patients

Background: Axial spondyloarthritis (axSpA) is an inflammatory, systemic rheumatic condition that mostly affects the axial skeleton. Tenascin-C (TN-C) is a hexameric glycoprotein of considerable size, upregulated in many inflammatory conditions, while Interleukin-17 (IL-17) a cytokine that plays an important role in SpA symptoms. Objective: to investigate the upregulation between the serum levels of TN-C and IL-17 in Iraqi axSpA patients and the disease characteristics. Patients and Methods: Seventy-four axSpA patients and 28 matched controls were studied. Fifty-four patients received a tumor necrosis factor inhibitor (TNFi) and 20 did not. Serum TN-C and IL-17 concentrations were determined using the ELISA technique. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was assessed. For statistical tests, Chi Square, Mann Whitney, Independent Samples T, and Pearson's correlation tests are used. Results: Patients mean age was 35.6±0.9 years, 65 males and 9 females, and disease duration was 5.18±0.6 years. 47.4% were smokers, 47% had inflammatory low back pain, and HLA-B27 was present in 91%. BASDAI mean was 6.1±0.4 in non-TNFi and 2.6±0.3 in those on TNFi. The serum TN-C concentration was significantly increased in patients, especially those on non-TNFi (79±9.6 pg/mL) compared to those on TNFi (69.1±3.2 pg/mL) and control (53±3.9 pg/mL) (p=0.003). Serum IL-17 was significantly elevated in those receiving TNFi (877.9±257 pg/mL) compared to non-TNFi (487.2±234 pg/mL) and control (182.4±36.6 pg/mL) (p=0.033). The TN-C significantly correlated with erythrocyte sedimentation rate (r=0.27, p=0.02) and with hemoglobin (Hb) concentration (r=0.26, p=0.02). TN-C and IL-17 were non-significantly related (r=0.14, p=0.2). Conclusions: axSpA Patients demonstrated high levels of serum TN-C, particularly in those not receiving TNFi, and high IL-17 levels in those receiving TNFi, suggesting that there is an association with tissue injury from the disease and stimulation of immunological and resident tissue cells. Patients who had not received TNFi showed significantly higher disease activity than others.

Tenascin-C in Heart Diseases-The Role of Inflammation.

Tenascin-C (TNC) is a large extracellular matrix (ECM) glycoprotein and an original member of the matricellular protein family. TNC is transiently expressed in the heart during embryonic development, but is rarely detected in normal adults; however, its expression is strongly up-regulated with inflammation. Although neither TNC-knockout nor -overexpressing mice show a distinct phenotype, disease models using genetically engineered mice combined with in vitro experiments have revealed multiple significant roles for TNC in responses to injury and myocardial repair, particularly in the regulation of inflammation. In most cases, TNC appears to deteriorate adverse ventricular remodeling by aggravating inflammation/fibrosis. Furthermore, accumulating clinical evidence has shown that high TNC levels predict adverse ventricular remodeling and a poor prognosis in patients with various heart diseases. Since the importance of inflammation has attracted attention in the pathophysiology of heart diseases, this review will focus on the roles of TNC in various types of inflammatory reactions, such as myocardial infarction, hypertensive fibrosis, myocarditis caused by viral infection or autoimmunity, and dilated cardiomyopathy. The utility of TNC as a biomarker for the stratification of myocardial disease conditions and the selection of appropriate therapies will also be discussed from a clinical viewpoint.

Generation of Transgenic Mice that Conditionally Overexpress Tenascin-C.

Tenascin-C (TNC) is an extracellular matrix glycoprotein that is expressed during embryogenesis. It is not expressed in normal adults, but is up-regulated under pathological conditions. Although TNC knockout mice do not show a distinct phenotype, analyses of disease models using TNC knockout mice combined with in vitro experiments revealed the diverse functions of TNC. Since high TNC levels often predict a poor prognosis in various clinical settings, we developed a transgenic mouse that overexpresses TNC through Cre recombinase-mediated activation. Genomic walking showed that the transgene was integrated into and truncated the Atp8a2 gene. While homozygous transgenic mice showed a severe neurological phenotype, heterozygous mice were viable, fertile, and did not exhibit any distinct abnormalities. Breeding hemizygous mice with Nkx2.5 promoter-Cre or α-myosin heavy chain promoter Cre mice induced the heart-specific overexpression of TNC in embryos and adults. TNC-overexpressing mouse hearts did not have distinct histological or functional abnormalities. However, the expression of proinflammatory cytokines/chemokines was significantly up-regulated and mortality rates during the acute stage after myocardial infarction were significantly higher than those of the controls. Our novel transgenic mouse may be applied to investigations on the role of TNC overexpression in vivo in various tissue/organ pathologies using different Cre donors.

Tenascin C promotes cancer cell plasticity in mesenchymal glioblastoma.

Interconversion of transformed non-stem cells to cancer stem cells, termed cancer cell plasticity, contributes to intra-tumor heterogeneity and its molecular mechanisms are currently unknown. Here, we have identified Tenascin C (TNC) to be upregulated and secreted in mesenchymal glioblastoma (MES GBM) subtype with high NF-κB signaling activity. Silencing TNC decreases proliferation, migration and suppresses self-renewal of glioma stem cells. Loss of TNC in MES GBM compromises de-differentiation of transformed astrocytes and blocks the ability of glioma stem cells to differentiate into tumor derived endothelial cells (TDEC). Inhibition of NF-κB activity or TNC knockdown in tumor cells decreased their tumorigenic potential in vivo. Our results uncover a link between NF-κB activation in MES GBM and high levels of TNC in GBM extracellular matrix. We suggest that TNC plays an important role in the autocrine regulation of glioma cell plasticity and hence can be a potential molecular target for MES GBM.

High serum levels of tenascin-C are associated with suicide attempts in depressed patients

The proteomic study reported that Tenascin-C might be a diagnostic biomarker for major depressive disorder, but clinical studies of this potential relationship are lacking. Here we examined the association between tenascin-C levels in serum and suicide attempts. Serum tenascin-C concentrations were compared among depressive patients who had not attempted suicide (n = 86), patients who had attempted it (n = 43), and healthy controls (n = 109). All participants were aged between 18 and 68 years. The association between concentration and suicide attempts was assessed by multivariate analysis after adjusting for sociodemographics, lifestyle and health indicators. Tenascin-C concentrations were higher in patients than in controls, and higher in patients who had attempted suicide than in patients who had not. Higher concentrations were associated with greater risk of attempting suicide. Among patients who had attempted suicide, tenascin-C concentrations were associated with severity of depression. Our results suggest that high tenascin-C levels in depressive patients correlate with suicide attempts and severity of depression. Tenascin-C may contribute to risk of suicide attempts in depressed patients.

Serum tenascin-C predicts severity and outcome of acute intracerebral hemorrhage

BackgroundTenascin-C is a matricellular protein related to brain injury. We studied serum tenascin-C in acute intracerebral hemorrhage (ICH) and examined the associations with severity and outcome following the acute event. MethodsTenascin-C samples were obtained from 162 patients with acute hemorrhagic stroke and 162 healthy controls. Poor 90-day functional outcome was defined as modified Rankin Scale score > 2. Early neurological deterioration (END) and hematoma growth (HG) were recorded at 24 h. ResultsPatients had higher tenascin-C levels than controls. Tenascin-C levels were positively correlated with hematoma volume or National Institutes of Health Stroke Scale score at baseline. Elevated tenascin-C levels were independently associated with END, HG, 90-day mortality and poor functional outcome. Moreover, tenascin-C levels significantly predicted END, HG and 90-day outcomes under receiver operating characteristic curves. ConclusionsAn increase in serum tenascin-C level is associated with an adverse outcome in ICH patients, supporting the potential role of serum tenascin-C as a prognostic biomarker for hemorrhagic stroke.

Multicomponent analysis of the tumour microenvironment reveals low CD8 T cell number, low stromal caveolin-1 and high tenascin-C and their combination as significant prognostic markers in non-small cell lung cancer.

The complex interplay of the tumour microenvironment (TME) and its role in disease progression and response to therapy is poorly understood. The majority of studies to date focus on individual components or molecules within the TME and so lack the power correlative analysis. Here we have performed a multi-parameter analysis of the TME in 62 resectable non-small cell lung cancer (NSCLC) specimens detailing number and location of immune infiltrate, assessing markers of cancer-associated fibroblasts, caveolin-1 and tenascin-C, and correlating with clinicopathological details, as well as markers of disease progression such as epithelial-to-mesenchymal transition (EMT). The influence of individual parameters on overall survival was determined in univariate and multivariate analysis and the combination of risk factors and interplay between components analysed. Low numbers of CD8 T cells, low stromal levels of caveolin-1 or high levels of tenascin-C were significant prognostic markers of decreased overall survival in both univariate and multivariate analysis. Patients with two or more risk factors had dramatically reduced overall survival and those with all three a median survival of just 7.5 months. In addition, low levels of tumour E-cadherin correlated with reduced immune infiltrate into the tumour nests, possibly linking EMT to the avoidance of CD8 T cell control. The multicomponent approach has allowed identification of the dominant influences on overall survival, and exploration of the interplay between different components of the TME in NSCLC.

Tenascin C to regulate the function of sHER3, an endogenous inhibitor of neuregulin signaling.

e23002 Background: HER3 expression is associated with poor prognosis in melanoma patients but the mechanistic basis has not been determined. An endogenous secreted isoform of HER3, p85-sHER3, has been shown by us to inhibit neuregulin-1 mediated, Akt-dependent breast and ovarian cancer cell growth in vitro. Here we demonstrate that p85-sHER3 also regulates neuregulin-dependent melanoma cell migration via an Akt- independent, tenascin C-dependent mechanism. Methods: Immunoblot analysis and RT-PCR were used to study HER3 and p85-sHER expression. Cell proliferation and chamber assays were conducted to determine the effect of p85-sHER3 on melanoma cell growth and migration. Mass spectrometry (MS) was performed to identify sHER3-interacting proteins. CRSPR in vitro editing methods were used to knock out tenascin C (TNC) expression. Results: HER3 and p85-sHER3 were expressed in 5 of 6 human melanoma-derived cell lines tested, with exception of SK-MEL-103 which did not express either gene product. Exogenous addition of 10 nM p85-sHER3 inhibited growth in 3 cells lines, although Akt phosphorylation was not reduced. Protein extracts from M14-MEL cell conditioned media were characterized by MS, and identified p85-sHER3 and TNC. Their association was confirmed by co-immunoprecipitation. sHER3 was further shown to inhibit neuregulin stimulated cell migration in 2 cell lines which exhibited high levels of TNC. CRSPR knockout of TNC in these cell lines (but not in control lines) eliminated sHER3 inhibition of neuregulin stimulated melanoma cell migration. Conclusions: Our results suggest that p85-sHER3, predominantly secreted by HER3-expressing melanoma cells, inhibits melanoma cell proliferation and migration via an Akt-independent mechanism, which is likely achieved through interaction(s) with TNC. TNC promotes an intermediate adhesive state favoring cell migration and this state appears to be mediated by Rho-associated kinase signaling. The Rho inhibitor, CCG-203971 has been shown to inhibit melanoma cell migration. Together, these results suggest the existence of a TNC and HER3-dependent signaling pathway in melanoma that regulates cell migration, and therefore may be correlated with poor patient survival.

Inflammatory markers and circulating extracellular matrix proteins in patients with chronic obstructive pulmonary disease and left ventricular diastolic dysfunction.

Left ventricular diastolic dysfunction (LVDD) is a frequent condition in chronic obstructive pulmonary disease (COPD). Tenascin-C (Tn-C) and matrix metalloproteinase-9 (MMP-9) are extracellular matrix proteins associated with myocardial fibrosis and wall remodeling because of inflammation. To determine whether the circulating levels of inflammatory markers, Tn-C and MMP-9 are associated with LVDD in COPD patients. Forty-two severe stable COPD patients (64 ± 8 years, 88% male, FEV1% 38 ± 5.7) and a control group (n = 11) were included. Pulmonary function tests and a Doppler echocardiography were performed on COPD patients. Baseline serum levels of C-reactive protein (CRP), leukocytes, fibrinogen, interleukins (IL) 6 and 8, Tn-C and MMP-9 were analyzed in all participants. COPD patients were classified in two groups: LVDD (n = 35) and non-LVDD (n = 7). Serum levels of IL-6 and CRP were higher in the LVDD group compared to the non-LVDD group [median(IQR)] [3.46 pg/mL (2.36-4.74) vs 1.87 pg/mL (1.10-3.28), P = 0.045] and [6.0 mg/L (3.0-13.0) vs 1.0 mg/L (1.0-2.3), P = 0.001], respectively. The same trend was observed in the analysis adjusted by age and BMI, being significant for CRP (P = 0.04). Circulating IL-6 was associated with the type of LVDD, being higher in the type-II (P = 0.046). Obese patients with COPD-LVDD showed a higher level of inflammatory markers (P = 0.021). Tn-C were significantly higher in patients with LVDD type-II compared to type-I [1422 ng/mL (826-1948) vs 781 ng/mL (640-1139), P = 0.015], without differences in MMP-9. Severe COPD patients with LVDD showed a different inflammatory pattern, suggesting a link between low-grade inflammation and the presence of LVDD. In COPD, high levels of Tn-C are related to LVDD type-II.

A new player in chronic kidney disease mineral and bone disorder: tenascin-C.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a condition frequently observed in CKD. The search for a reliable and easy to use biomarker in the diagnosis of CKD-MBD is continuing. Tenascin-C (TN-C) is an important extracellular (ECM) protein synthesized by osteoblasts during bone growth and morphogenesis. The purpose of this study was to assess the relation between inflammation and MBD and TN-C in HD patients and to identify a new marker that can be used to help diagnose CKD-MBD. 136 HD patients and 22 healthy controls were enrolled in this cross-sectional, observational multicenter study. Once patients' demographic and biochemical parameters had been recorded, peripheral blood samples were collected for TN-C measurement before the mid-week HD session. The relationship between TN-C levels and demographic and biochemical parameters was then assessed. TN-C levels were significantly higher in the HD patient than in the control group (P<.001). Intact parathormone (iPTH) affected TN-C levels in the HD patient group. TN-C levels was significantly higher in both the high (>300 pg/ml) and low iPTH groups (<150 pg/ml) compared to the 150-300 pg/ml iPTH group (P<.001, <.001 respectively). This study showed, for the first time in the literature, high levels of TN-C in the low and high iPTH groups and that this elevation was associated with iPTH. We think that if our study is supported by further research, TN-C can be a biomarker capable of use in diagnosing CKD-MBD.

Tenascin-C is a possible mediator between initial brain injury and vasospasm-related and -unrelated delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

Tenascin-C (TNC), a matricellular protein, exerts diverse functions, including tissue remodeling and apoptosis, and is induced in cerebrospinal fluid (CSF) after aneurysmal subarachnoid hemorrhage (SAH). The purpose of this study was to examine the relationships among CSF TNC levels, initial brain injury, delayed cerebral ischemia (DCI), and vasospasm after SAH. CSF TNC levels were measured in 30 patients with aneurysmal SAH of Fisher computed tomography (CT) group III who were treated microsurgically or endovascularly with CSF drainage within 24 h of SAH. Admission World Federation of Neurosurgical Societies (WFNS) grade was supposed to indicate the severity of initial brain injury. Cerebral vasospasm was defined as narrowed (≥ 25 %) cerebral arteries demonstrated by angiography. DCI was defined as any neurological deterioration presumed related to ischemia that persisted for ≥ 1 h. Higher CSF TNC levels were correlated with worse admission WFNS grades. Vasospasm was aggravated with higher TNC levels. DCI occurred regardless of the degree of vasospasm but was associated with TNC induction. Multivariate analyses showed that higher TNC levels and vasospasm were independent predictors of DCI occurrence. SAH (initial brain injury) that is more severe induces more TNC, which may cause the subsequent development of both vasospasm and vasospasm-unrelated secondary brain injury, leading to DCI.

Clinical significance of serum tenascin-c levels in epithelial ovarian cancer.

Tenascin-C (TNC) is an extracellular matrix protein that is expressed at low levels in normal adult tissue but is highly expressed around many tumors including ovarian tumors. The objective of this study was to determine the clinical significance of the serum levels of TNC in epithelial ovarian cancer (EOC) patients. A total of 50 patients with a pathologically confirmed diagnosis of EOC were included in this study. Serum TNC levels were determined by the solid-phase sandwich enzyme-linked immunosorbent assay (ELISA) method. Age- and sex- matched 28 healthy controls were included in the analysis. Median age of the patients was 56.5 years old, range 22 to 83 years. Majority of the patients had advanced disease (FIGO stage III-IV) (90 %). The median serum TNC levels were found significantly higher in EOC patients (130.5 pg/mL) compared to healthy controls (90.1 pg/mL) (p = 0.03). We found no correlation between serum TNC levels and any prognostic parameters analyzed, including age of the patients, histology, tumor grade, stage of the disease, and response to chemotherapy. Survival analysis did not show statistically significant effect of serum TNC concentration on progression-free and overall survival (p = 0.36 and p = 0.19, respectively). However, patients with high serum TNC levels tend to have poor overall survival. In conclusion, although serum TNC levels are elevated, it has no predictive or prognostic roles on survival in EOC patients.

Assessment of Tenascin‐C Levels in Ventricular Noncompaction/Hypertrabeculation Patients: A Cross‐Sectional Study

Ventricular noncompaction/hypertrabeculation (NC/HT) is a rare form of congenital cardiomyopathy. We aimed to investigate the presence of serum tenascin-C (TN-C) in adult patients with NC/HT and evaluate its value. Serum TN-C levels were measured by ELISA in 50 NC/HT patients both with/without systolic dysfunction and in 23 normal controls. Systolic dysfunction was defined as ejection fraction (EF) ≤ 40. Mann-Whitney U-test and ROC curve analysis were done. Of 49 NC/HT patients, 24 (49%) patients had systolic dysfunction (mean age 36 ± 15) and 25 patients (51%) had normal systolic function (mean age 36 ± 17). The ages between groups were not different. The mean levels of serum TN-C in patients with or without systolic dysfunction were 26 ± 10 ng/mL and 26 ± 8 ng/mL respectively, compared to normal controls, 7 ± 2 ng/mL (P < 0.001). No significance was observed between 2 groups of NC/HT patients regarding TN-C levels (P = 0.8). The ROC curve analysis revealed that a TN-C value of 11.7 ng/mL identified patients with NC/HT with 100% sensitivity and specifity. High serum TN-C levels are present in adult NC/HT cardiomyopathy even when left ventricular systolic function remains normal. Also, serum TN-C levels could be regarded as a candidate biomarker in the diagnosis of NC/HT which needs to be tested in larger prospective studies.

Postmortem serum tenascin-C (TN-C) concentrations in forensic autopsy cases: A pilot study

In forensic investigations, autopsy findings offer major clues for the diagnosis of the cause of death. Thus, various clinical biochemical markers are now being tested to complement conventional investigation in the field of forensic medicine. In this study, we focused on tenascin-C (TN-C), a glycoprotein present in the extracellular matrix and expressed in pathological states. We reviewed autopsy cases for a 4-year period (2006-2009) using autopsy records, and analyzed the blood serum concentrations of TN-C and C-reactive protein (CRP) in these cases (N=101). The TN-C levels were relatively higher in the postmortem serum samples than in the samples from healthy individuals, and in cases of head injury, both TN-C and CRP levels were high in the postmortem serum sample. Moreover, high TN-C levels were observed particularly in cases with a long survival period. These findings indicate that postmortem serum TN-C levels may represent a useful tool for identifying the cause of specific fatal traumas.

Serum tenascin-C levels as a prognostic biomarker of heart failure events in patients with hypertrophic cardiomyopathy

Although serum tenascin-C (TN-C) levels are related to left ventricular (LV) remodeling in patients with myocardial infarction and are useful as a prognostic biomarker of heart failure in patients with dilated cardiomyopathy, the clinical significance of TN-C levels has not yet been studied in patients with hypertrophic cardiomyopathy (HCM). Therefore, the purpose of this study is to elucidate whether serum TN-C levels are a prognostic biomarker for heart failure in patients with HCM. The relationship between serum TN-C levels and heart failure events was studied in 36 patients with HCM during follow-up. Levels of serum TN-C were 28±13 ng/ml (range 11-80 ng/ml). Although patients with LV systolic impairment showed higher TN-C levels than those with preserved LV systolic function (33±11 ng/ml vs. 27±14 ng/ml; p=0.16), TN-C levels were not related to any echocardiographic parameters. During the follow-up period of 4.8±1.4 years, heart failure events were observed in six patients and TN-C levels in patients with events were higher than those in patients without events. Kaplan-Meier analysis showed that the prognosis was worse in patients with high TN-C levels (≥39.2 ng/ml) than in those with low TN-C levels. Heart failure events were more frequently observed in patients with high serum TN-C levels than in those with low TN-C levels. Serum TN-C levels may be a new prognostic biomarker for heart failure in patients with HCM.

Cerebrospinal Fluid Tenascin-C in Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Tenascin-C (TNC) has been reported to be a useful biomarker for the activity of inflammatory diseases. This study investigated the association between TNC levels in the cerebrospinal fluid (CSF) and symptomatic vasospasm after aneurysmal subarachnoid hemorrhage (SAH), and the prognostic value of TNC levels. TNC levels were measured in CSF in 33 consecutive patients diagnosed with aneurysmal SAH of Fisher computed tomography group III and were compared between those with and without subsequent cerebral vasospasm. Factors influencing symptomatic vasospasm were determined using multivariate logistic regression analyses. The receiver-operating characteristic curve technique was used to assess specificity and sensitivity in the prediction of symptomatic vasospasm. The CSF TNC levels peaked immediately after SAH and were significantly higher in patients who subsequently developed symptomatic vasospasm than in those who did not. On multivariate analyses, higher TNC levels in the CSF (odds ratio, 1.059; 95% confidence interval, 1.023-1.096; P<0.001) and World Federation of Neurosurgical Societies grades IV to V on admission (odds ratio, 3.238; 95% confidence interval, 1.033-10.152; P<0.05) significantly predicted symptomatic vasospasm. To predict the onset of symptomatic vasospasm, 16.2 ng/mL was considered as an appropriate cut-off value for CSF TNC on days 1 through 6, giving a sensitivity of 81.0% and a specificity of 79.5% (negative and positive predictive values: 82.3% and 76.7%, respectively). TNC in the CSF may be a useful biomarker for predicting subsequent development of cerebral vasospasm.

The Relationship between Tenascin-C Levels and the Complexity of Coronary Lesion after Myocardial Infarction

The increase of tenascin-C levels after myocardial infarction has been demonstrated by previous studies. The relationship between tenascin-C and the grade of stenosis in the infarct-related coronary artery was indeterminate. The aim of this study was to evaluate the relationship between tenascin-C levels and total occlusion after acute myocardial infarction. Fifty-nine patients with subacute anterior myocardial infarction were divided into two groups according to their having a totally or subtotally occluded left anterior desending artery. Plasma tenascin-C, troponin I, CK-MB, uric acid, mean platelet volume, and lipid profile levels were also measured. The history of the smoking rate, hypertension and diabetes mellitus were similar in both groups. Hemoglobin, mean platelet volume, serum creatinine, CK-MB, troponin I, serum lipid profile and uric acid levels were similar in the two groups. The CRP and tenascin-C levels were significantly higher in the total occlusion group. Tenascin-C levels were highest in patients with proximal LAD total occlusion and lowest in patients with subtotal LAD occlusion. The tenascin-C levels were correlated with the grade of stenosis (r = 0.602, p < 0.001). This study demonstrates that higher tenascin-C levels were related with the total occlusion and inflammation after MI.

Transcriptional Regulation of the Endogenous Danger Signal Tenascin-C: A Novel Autocrine Loop in Inflammation

Inappropriate expression of proinflammatory mediators underpins the pathogenesis of autoimmune disease and tumor metastasis. The extracellular matrix glycoprotein tenascin-C is an endogenous activator of innate immunity that promotes the synthesis of inflammatory cytokines via activation of TLR4. Little tenascin-C is observed in most healthy adult tissues, but expression is specifically upregulated at sites of inflammation. Moreover, high levels of tenascin-C are associated with chronic inflammation and found in the tumor stroma. In this study, we show that the expression of tenascin-C is induced in immune myeloid cells activated by a variety of inflammatory stimuli, including specific TLR ligands. Its synthesis is transcriptionally regulated and requires the specific activation of AKT/PI3K and NF-kappaB signaling pathways. Using a bioinformatic approach, we identified a large number of conserved noncoding regions throughout the tenascin-C genomic locus that may contribute to its transcriptional regulation during inflammation. We also demonstrate that tenascin-C expression is transient during acute inflammation. In contrast, persistently high levels of expression occur in the inflamed synovium of joints from rheumatoid arthritis patients. Thus, misregulated expression of this endogenous danger signal may promote an autocrine loop of inflammation and contribute to the persistence of inflammation in autoimmune diseases or to tumor egress and invasion during metastasis.

Tenascin-C may aggravate left ventricular remodeling and function after myocardial infarction in mice

Tenascin-C (TN-C) is an extracellular matrix glycoprotein with high bioactivity. It is expressed at low levels in normal adult heart, but upregulated under pathological conditions, such as myocardial infarction (MI). Recently, we (Ref. 34) reported that MI patients with high serum levels of TN-C have a greater incidence of maladaptive cardiac remodeling and a worse prognosis. We hypothesized that TN-C may aggravate left ventricular remodeling. To examine the effects of TN-C, MI was induced by ligating coronary arteries of TN-C knockout (KO) mice under anesthesia and comparing them with sibling wild-type (WT) mice. In WT+MI mice, TN-C expression was upregulated at day 1, peaked at day 5, downregulated and disappeared by day 28, and the molecule was localized in the border zone between intact myocardium and infarct lesions. The morphometrically determined infarct size and survival rate on day 28 were comparable between the WT+MI and KO+MI groups. Echocardiography and hemodynamic analyses demonstrated left ventricular end-diastolic diameter, myocardial stiffness, and left ventricular end-diastolic pressure to be significantly increased in both WT+MI and KO+MI mice compared with sham-operated mice. However, end-diastolic pressure and dimension and myocardial stiffness of KO+MI were lower than those of the WT+MI mice. Histological examination revealed normal tissue healing, but interstitial fibrosis in the residual myocardium in peri-infarcted areas was significantly less pronounced in KO+MI mice than in WT+MI mice. TN-C may thus accelerate adverse ventricular remodeling, cardiac failure, and fibrosis in the residual myocardium after MI.