Tenascin-C and mechanotransduction in the development and diseases of cardiovascular system

Living tissue is composed of cells and extracellular matrix (ECM). In the heart and blood vessels, which are constantly subjected to mechanical stress, ECM molecules form well-developed fibrous frameworks to maintain tissue structure. ECM is also important for biological signaling, which influences various cellular functions in embryonic development, and physiological/pathological responses to extrinsic stimuli. Among ECM molecules, increased attention has been focused on matricellular proteins. Matricellular proteins are a growing group of non-structural ECM proteins highly up-regulated at active tissue remodeling, serving as biological mediators. Tenascin-C (TNC) is a typical matricellular protein, which is highly expressed during embryonic development, wound healing, inflammation, and cancer invasion. The expression is tightly regulated, dependent on the microenvironment, including various growth factors, cytokines, and mechanical stress. In the heart, TNC appears in a spatiotemporal-restricted manner during early stages of development, sparsely detected in normal adults, but transiently re-expressed at restricted sites associated with tissue injury and inflammation. Similarly, in the vascular system, TNC is strongly up-regulated during embryonic development and under pathological conditions with an increase in hemodynamic stress. Despite its intriguing expression pattern, cardiovascular system develops normally in TNC knockout mice. However, deletion of TNC causes acute aortic dissection (AAD) under strong mechanical and humoral stress. Accumulating reports suggest that TNC may modulate the inflammatory response and contribute to elasticity of the tissue, so that it may protect cardiovascular tissue from destructive stress responses. TNC may be a key molecule to control cellular activity during development, adaptation, or pathological tissue remodeling

Locally applied cilostazol suppresses neointimal hyperplasia by inhibiting tenascin-C synthesis and smooth muscle cell proliferation in free artery grafts

AbstractObjectiveAccumulation of smooth muscle cells and extracellular matrix in the intima of artery bypass grafts induces neointimal hyperplasia, resulting in graft failure. We investigated the inhibitory effect of locally applied cilostazol, an inhibitor of cyclic adenosine monophosphate phosphodiesterase III, on neointimal hyperplasia and the role of tenascin-C synthesis and smooth muscle cell proliferation in free artery grafts.Methods and resultsWe established a distal anastomotic stricture model of free artery graft stenosis using rat abdominal aorta. In this model, neointimal hyperplasia was observed not only in the distal anastomotic site but also in the graft body at postoperative day 14 and was markedly progressed at day 28. Strong expression of tenascin-C was found in the media and neointima of the graft body. When cilostazol was locally administered around the graft using Pluronic gel, neointimal hyperplasia of the graft was significantly suppressed in comparison with gel-treated control graft. The mean neointima/media area ratio was reduced by 86.6% for the graft body and by 75.8% for the distal anastomotic site versus the control. Cilostazol treatment decreased cell proliferation and tenascin-C expression in the neointima. In an in vitro experiment using cultured smooth muscle cells isolated from rat aorta, cilostazol completely suppressed the tenascin-C mRNA expression induced by platelet-derived growth factor-BB.ConclusionA single topical administration of cilostazol may suppress neointimal hyperplasia by inhibiting cell proliferation and tenascin-C synthesis in free artery grafts, presenting the potential for clinical use in vascular surgery

Case Report: Acute Eosinophilic Myocarditis With a Low-Flow Heart Failure With Preserved Ejection Fraction Phenotype

Eosinophilic myocarditis is a rare subtype of myocarditis characterized by myocardial eosinophilic infiltration, and it is potentially fatal if left untreated. Although endomyocardial biopsy (EMB) is a cornerstone for the histological diagnosis of acute eosinophilic myocarditis (AEM), as it is an invasive procedure and has a low diagnostic accuracy, the diagnosis of AEM with hemodynamic instability remains challenging. We describe a case of AEM presenting as low-flow heart failure with preserved ejection fraction (HFpEF), with rapid progression to cardiogenic shock. The constellation of peripheral eosinophilia, increased left ventricular wall thickness, and HFpEF raised the suspicion of AEM. Contrast-enhanced computed tomography (CT) scan revealed heterogeneous hypoenhancement localized in the basal-to-mid septal and mid anterolateral walls of the left ventricle, strongly suggestive of acute inflammation. Based upon these findings, we performed CT-guided EMB, which lead to a definitive diagnosis. Subsequent high-dose corticosteroids allowed a rapid and dramatic recovery and normalization of cardiac structure and function. This case highlights the clinical importance of assessing AEM as a rare cause of HFpEF and the usefulness of CT-guided EMB in patients with hemodynamic instability

14-Cmethionine uptake as a potential marker of inflammatory processes after myocardial ischemia and reperfusion

A relationship between L-[methyl-11C]methionine (11C-methionine) uptake and angiogenesis has been suggested in gliomas. However, methionine uptake in myocardial ischemia and reperfusion has received little attention. We investigated the serial changes and mechanisms of 14-Cmethionine uptake in a rat model of myocardial ischemia and reperfusion. Methods: The left coronary artery was occluded for 30 min, followed by reperfusion for 1-28 d. At the time of the study, 14-Cmethionine (0.74 MBq) and 201Tl (14.8 MBq) were injected intravenously at 20 and 10 min before sacrifice, respectively. One minute before sacrifice, the left coronary artery was reoccluded, and 99mTc-hexakis-2-methoxyisobutylisonitrile (150-180 MBq) was injected to verify the area at risk. Histologic sections of the heart were immunohistochemically analyzed using anti-CD68, anti-smooth-muscle a-actin (SMA), and antitroponin I and compared with the autoradiography findings. Results: Both 14Cmethionine (uptake ratio, 0.71 ± 0.13) and 201Tl uptake were reduced in the area at risk at 1 d after reperfusion. However, 3 d after reperfusion, an increased 14-Cmethionine uptake (1.79 ± 0.23) was observed corresponding to the area of still-reduced 201Tl uptake, and the 14-Cmethionine uptake gradually declined until 28 d. The increased 14-Cmethionine uptake area at 3 and 7 d corresponded well to the macrophage infiltrations demonstrated by positive CD68 staining. Anti-SMA staining appeared at 7 d, after which CD68 staining was gradually replaced by the SMA staining, suggesting that methionine uptake in the early phase after ischemia and reperfusion might reflect inflammatory activity. Conclusion: 14-Cmethionine accumulated in the infarcted area, and its uptake corresponded closely to macrophage infiltration at 3-7 d after reperfusion. Methionine imaging may be useful for inflammatory imaging early after myocardial infarction. COPYRIGHT © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc

Comprehensive phenotypic and genomic characterization of venous malformations

Hirose K., Hori Y., Ozeki M., et al. Comprehensive phenotypic and genomic characterization of venous malformations. Human Pathology 145, 48 (2024); https://doi.org/10.1016/j.humpath.2024.02.004.Venous malformations (VMs) are the most common vascular malformations. TEK and PIK3CA are the causal genes of VMs, and may be involved in the PI3K/AKT pathway. However, the downstream mechanisms underlying the TEK or PIK3CA mutations in VMs are not completely understood. This study aimed to identify a possible association between genetic mutations and clinicopathological features. A retrospective clinical, pathological, and genetic study of 114 patients with VMs was performed. TEK, PIK3CA, and combined TEK/PIK3CA mutations were identified in 49 (43%), 13 (11.4%), and 2 (1.75%) patients, respectively. TEK-mutant VMs more commonly occurred in younger patients than TEK and PIK3CA mutation-negative VMs (other-mutant VMs), and showed more frequent skin involvement and no lymphocytic aggregates. No significant differences were observed in sex, location of occurrence, malformed vessel size, vessel density, or thickness of the vascular smooth muscle among the VM genotypes. Immunohistochemical analysis revealed that the expression levels of phosphorylated AKT (p-AKT) were higher in the TEK-mutant VMs than those in PIK3CA-mutant and other-mutant VMs. The expression levels of p-mTOR and its downstream effectors were higher in all the VM genotypes than those in normal vessels. Spatial transcriptomics revealed that the genes involved in “blood vessel development”, “positive regulation of cell migration”, and “extracellular matrix organization” were up-regulated in a TEK-mutant VM. Significant genotype-phenotype correlations in clinical and pathological features were observed among the VM genotypes, indicating gene-specific effects. Detailed analysis of gene-specific effects in VMs may offer insights into the underlying molecular pathways and implications for targeted therapies

Effect of postconditioning on dynamic expression of tenascin-C and left ventricular remodeling after myocardial ischemia and reperfusion

金沢大学疾患モデル総合研究センターBackgroundTenascin-C (TNC), an extracellular matrix glycoprotein, is expressed transiently in distinct areas in association with active tissue remodeling. This study aimed to explore how ischemic postconditioning (PC) affects myocardial expression of TNC and ventricular remodeling using 125I-labeled anti-TNC antibody (125I-TNC-Ab) in a rat model of ischemia and reperfusion.MethodsIn control rats (n = 27), the left coronary artery (LCA) was occluded for 30 min followed by reperfusion for 1, 3, 7, and 14 days. PC (n = 27) was performed just after the reperfusion. At the time of the study, 125I-TNC-Ab (1.0 to 2.5 MBq) was injected. Six to 9 h later, to verify the area at risk, 99mTc-MIBI (100 to 200 MBq) was injected intravenously just after the LCA reocclusion, with the rats sacrificed 1 min later. Dual tracer autoradiography was performed to assess 125I-TNC-Ab uptake and area at risk. To examine the ventricular remodeling, echocardiography was performed 2 M after reperfusion in both groups.ResultsIn control rats, 125I-TNC-Ab uptake ratio at 1 day after reperfusion was 3.73 ± 0.71 and increased at 3 days (4.65 ± 0.87), followed by a significant reduction at 7 days (2.91 ± 0.55, P < 0.005 vs 3 days) and14 days (2.01 ± 0.17, P < 0.005 vs 1 and 3 days). PC attenuated the 125I-TNC-Ab uptake throughout the reperfusion time from 1 to 14 days; 2.59 ± 0.59 at 1 day, P < 0.05: 3.10 ± 0.42 at 3 days, P < 0.005: 1.93 ± 0.37 at 7 days, P < 0.05: 1.40 ± 0.07 at 14 days, P < 0.001. In echocardiography, PC reduced the ventricular end-diastolic and systolic dimensions (1.00 ± 0.06 cm to 0.83 ± 0.14 cm (P < 0.05) and 0.90 ± 0.15 cm to 0.62 ± 0.19 cm (P < 0.05), respectively) and prevented a decline of ventricular percentage fractional shortening (10.5 ± 3.7 to 28.2 ± 10.7, P < 0.005).ConclusionsThese data indicate that 125I-TNC-Ab imaging may be a way to monitor myocardial injury, the subsequent repair process, and its response to novel therapeutic interventions like PC by visualizing TNC expression

Dynamic expression of tenascin-C after myocardial ischemia and reperfusion: Assessment by125i-anti-tenascin-c antibody imaging

金沢大学疾患モデル総合研究センターTenascin-C, an extracellular matrix glycoprotein, appears only in the early stages of embryonic development. It is not normally expressed in the adult heart but does reappear transiently in distinct areas in association with active tissue remodeling. The aim of this study was to explore serial changes in the expression of tenascin-C after myocardial ischemia and reperfusion, using 125I-labeled anti-tenascin-C antibody (125I-TNC-Ab) in a rat model of acute ischemia and reperfusion. Methods: The left coronary artery was occluded for 20or30min, followedbyreperfusion for 1, 3, or 7 d in rats with 20 min of ischemia and for 1, 3, 7, 14, or 28 d inrats with30min ofischemia.Atthe timeofthe study,125I-TNC-Ab (1.0-2.5 MBq) was injected. Three to 5 h later, to verify the area at risk,99mTc- methoxyisobutylisonitrile (100-200 MBq) was injected intravenously just after the left coronary artery reocclusion and the rats were sacrificed 1 min later. Dual-tracer autoradiography was performed to assess125I-TNC-Ab uptake and the area at risk. Results: In rats with 20 min of ischemia, 125I-TNC-Ab uptake peaked at 3 d after reperfusion, followed by faint uptake after 7 d (uptake ratios at 1, 3, and 7 d after reperfusion were 1.81 ± 0.53, 2.46 ± 0.79, and 1.23 ± 0.17, respectively [P < 0.05 vs. 3 d]). In rats with 30 min of ischemia, uptake was high at 1 and 3 d after reperfusion (2.99 ± 0.90 and 2.71 ± 0.80, respectively), decreased at 7 and 14 d (1.94 ± 0.23 and 2.06 ± 0.37, respectively), and was weak at 28 d (1.47 ± 0.27, P < 0.005 vs. 1 d, P < 0.05 vs. 3 d). Conclusion: These data indicate that125I-TNC-Ab imaging may be a way to monitor myocardial injury and its repair process after ischemia and reperfusion by visualizing tenascin-C expression. COPYRIGHT © 2010 by the Society of Nuclear Medicine, Inc

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

The Pathogenesis of Cardiac Fibrosis: A Review of Recent Progress

Fibrosis is defined as the excessive deposition of extracellular matrix (ECM) proteins in the interstitium. It is an essential pathological response to chronic inflammation. ECM protein deposition is initially protective and is critical for wound healing and tissue regeneration. However, pathological cardiac remodeling in excessive and continuous tissue damage with subsequent ECM deposition results in a distorted organ architecture and significantly impacts cardiac function. In this review, we summarized and discussed the histologic features of cardiac fibrosis with the signaling factors that control it. We evaluated the origin and characteristic markers of cardiac fibroblasts. We also discussed lymphatic vessels, which have become more important in recent years to improve cardiac fibrosis