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The role of tenascin C in cardiovascular disease

Jonathan Golledge, Paula Clancy, Jane Maguire, Lisa Lincz, Simon Koblar
DOI: http://dx.doi.org/10.1093/cvr/cvr183 19-28 First published online: 28 June 2011

Abstract

The extracellular matrix protein tenascin C (TnC) is expressed in a variety of embryonic tissues, but its expression in adult arteries is co-incident with sites of vascular disease. TnC expression has been linked to the development and complications of intimal hyperplasia, pulmonary artery hypertension, atherosclerosis, myocardial infarction, and heart failure. This review identifies the growing collection of evidence linking TnC with cardiovascular disease development. The transient upregulation of this extracellular matrix protein at sites of vascular disease could provide a means to target TnC in the development of diagnostics and new therapies. Studies in TnC-deficient mice have implicated this protein in the development of intimal hyperplasia. Further animal and human studies are required to thoroughly assess the role of TnC in some of the other pathologies it has been linked with, such as atherosclerosis and pulmonary hypertension. Large population studies are also warranted to clarify the diagnostic value of this extracellular matrix protein in cardiovascular disease, for example by targeting its expression using radiolabelled antibodies or measuring circulating concentrations of TnC.

  • Cardiovascular disease
  • Extracellular matrix protein
  • Tenascin C

1. Introduction

Tenascin C (TnC) is a large extracellular matrix glycoprotein and was the first member identified of a family of four structurally similar proteins, including tenascin R, W and X.13 During early development, TnC is transiently expressed at a number of sites throughout the embryo, such as neural crest, central nervous system, lungs, and cardiovascular system.1 Despite this implied function during embryogenesis, knockout mice models of TnC grow to maturity without any overt signs of abnormalities.4 In normal adult tissue, only low levels of TnC are found. Higher levels of TnC expression have been reported in areas of wound healing, cancer development, and cardiovascular disease.1 Given this localization of TnC to sites of pathology, there has been increasing interest in assessing the role of this glycoprotein in disease development and targeting the protein in both diagnosis and therapy for a variety of pathologies.1 In this review, we summarize previous studies which have examined the expression and potential influence of TnC in cardiovascular disease.

2. Structure of TnC

The structure of TnC is relevant to its functions in health and disease and has been described in detail in previous reviews.13 TnC polypeptides are made up of a number of domains (Figure 1A) and include:

  1. An amino-terminal Tn assembly domain (TA) which is responsible for interactions between TnC polypeptides important in assembly of the multimeric protein;

  2. A contiguous group of repeats of epidermal growth factor-like domains;

  3. A series of fibronectin type III domains;

  4. A distal globular fibrinogen-homology domain.

While TnC is encoded by a single gene located at 9q33 in man, alternative splicing of mRNA can result in a large number of different isoforms with between 1 and 6 extra fibronectin type III domains (A1, A2, A4, B, C, and D) (Figure 1B). Ultimately, six TnC polypeptides can be assembled into a six armed structure referred to as a hexabrachion via interaction at the TA domains. This form of TnC has been identified within the extracellular matrix such as that present during embryonic development. The relative expression of different forms of TnC present in diseased adult tissue and circulating in the blood has been poorly described.

Figure 1

Structure of Tenascin C. (A) This diagram has been adapted from previous work using predicted domain boundaries to determine the overall structure of the protein. A recent study suggested the earlier delineations derived from reverse transcription polymerase chain reaction and western blotting [(B) shown below the main structure] had several flaws and did not correlate to the natural domain boundaries particularly in the A1–4 region.98 The N-terminal domain is called the tenascin assembly domain (TA) and is involved in the formation of the quarternary hexabrachion structure. Within this region, there is a heat shock protein 33 motif probably responsible for TnC aggregation within the cell.98 The next region includes 14 epidermal growth factor (EGF) like repeats which are quite consistent. The EGF-like repeat domain modulates cell adhesion and cell motility.99 This region is considered to be counter adhesive for fibroblasts, neurons, and glia and may be involved in neuronal migration and axon path finding during development.1 The following region contains the fibronectin (FN) III like repeats. The FN-III repeats vary considerably in amino acid sequence and have a variety of ligands.100 The final C-terminal domain is the fibrinogen (FG)-like domain. This domain is the region of the protein that binds to toll-like receptor (TLR)-4 as an endogenous ligand.51 Due to alternative splicing of pre-mRNA of the FN III-like repeats, 6–12, TnC exists as a number of isoforms with varying functions and sizes. The smallest isoform has a predicted molecular weight of 171.3 kDa and is missing repeats 6–12. The largest isoform with a predicted molecular mass of 240.8 kDa has all the FN III-like repeats included.101 TnC is also glycosylated102 giving rise to the range of sizes reported for the various isoforms, e.g. the large isoform has a reported size range of 280–350 kDa.

3. TnC interactions and signalling pathways

Associated with its complex structure, TnC has the capacity to interact with several different cell surface receptors. Different parts of the TnC protein have been ascribed to binding different receptors.1,3 The epidermal growth factor-like domains can bind the epidermal growth factor receptor. The third fibronectin type III repeat binds αvβ3 and other integrins promoting adhesion. The variable spliced A-D fibronectin type III repeats bind annexin II thereby inhibiting adhesion. The variable splice region has also been shown to interact with F3/contactin and α7β1 integrin.3 Thus, different isoforms of TnC would be expected to have different functional effects, although this has not been clearly defined.

4. In vitro studies assessing the determinants of TnC production and the interaction of TnC with vascular cells

The determinants of TnC expression have been examined in vitro in a variety of cells relevant to vascular disease, including vascular smooth muscle cells (VSMCs), endothelial cells, and monocyte-macrophages (Table 1).526 Overall, a range of factors implicated in cardiovascular disease, including cytokines, angiotensin II, and haemodynamic forces appear to be able to upregulate TnC expression in vitro. A number of medications have been reported to reduce TnC expression, including steroids, cilostazol, and non-steroidal anti-inflammatory drugs.12,15,24 Identified intra-cellular regulators of TnC expression in vascular cells include homeobox transcription factor Prx1, Rho, and extracellular signal-regulated kinases.11,1820 TnC expression has been shown to be under post-transcription control in non-vascular sites, such as within breast cancer metastases, where micro RNAs, including miR-355, have been shown to control TnC expression.27

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Table 1

Determinants of TnC expression in vitro in a variety of cells relevant to cardiovascular disease

Upregulators of TnCCell type studiedTnC form induced
Prostaglandin E2Mouse VSMCs5mRNA
LPS and other TLR ligandsMonocyte-derived cells such as macrophages6mRNA and protein
Wnt pathwayMouse pulmonary artery VSMCs7mRNA and protein
CD137 ligationRAW264.7 (murine myeloid cell line)8mRNA
ERK 1/2 mitogen-activated protein kinasesHuman pulmonary artery VSMCs9mRNA and protein
RhoA and Rho kinase ROCKRat pulmonary artery endothelial cells10,11mRNA
Interleukin-4Human peripheral blood-derived macrophages12mRNA
Cyclic stretchHuman aortic VSMCsmRNA and protein
Rat aortic VSMCs13,14
Platelet-derived growth factorRat aortic VSMC1517mRNA and protein including three isoforms (210, 220, and 250 kDa)
Prx1 (homeobox transcription factor)VSMC cell line18mRNA
Denatured collagen (via β3 integrin and ERK 1/2)VSMC cell line19,20mRNA and protein
Angiotensin IIHuman aortic VSMCmRNA and protein
Rat aortic VSMC
Human aortic endothelial cells16,17,21,22
Transforming growth factor betaHuman aortic VSMCmRNA and protein
Rat aortic VSMC
Human aortic endothelial cells17,21
Downregulators of TnCCell type studiedTnC form downregulated
Shear stress mimicking atheroprone flowHuman iliac vein endothelial and VSMC co-culture23mRNA
DexamethasoneHuman peripheral blood-derived macrophages12mRNA
CilostazolRat aortic VSMC15mRNA
Glafenine hydrochloride (NSAID)Human aortic VSMCs24Protein
9-cis retinoid acidHuman aortic VSMCs25Protein
Polymerized (compared to monomer) type 1 collagenHuman umbilical artery VSMCs26mRNA
  • TnC, Tenascin C; LPS, lipopolysaccharide; TLR, toll-like receptor; Wnt, wingless; VSMC, vascular smooth muscle cell; NSAID, non-steroidal anti-inflammatory drugs.

The actions of TnC have also been examined in vitro employing a range of cell types and TnC fragments (Table 2).10,20,21,2850 TnC has been reported to promote angiogenesis and release of pro-inflammatory cytokines and MMPs. TnC has also been reported to inhibit T cell proliferation and activation in vitro. The effects of TnC within in vitro studies seem to vary according to the fragment of TnC employed and the cell type studied. The region of TnC which contains the fibronectin type III repeats, and which varies by isoform type (Figure 1), appears to control the ability of TnC to influence cell adhesion.21,40,42,46,47 The epidermal growth factor-like domains of TnC have been suggested to control cell survival, while the distal globular fibrinogen-homology domain has been associated with stimulating cytokine production.31,51

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Table 2

Reports of the effects of TnC on cells relevant to cardiovascular disease in vitro

TnC form or interventionCell typeEffects
TnC fragment (A2 isoform)Human dermal microvascular endothelial cellsProliferation inhibited30
TnC from commercial company (Chemicon)Rat cardiac microvascular endothelial cellsPromotes response to angiogenic signals, such as PDGF and VEGF10
TnC from commercial company (Chemicon)Bovine and human retinal endothelial cellsPromotes endothelial cell tube formation and branching32
Recombinant chick TnCBovine aortic endothelial cellsStimulates actin cytoskeletal reorganization typical of sprouting endothelial cells39
Large and small splice variants of TnCBovine aortic endothelial cellsTnC fragment containing Fn A-D induces loss of focal adhesion by binding annexin II46,47
TnC blocking antibodyBovine aortic endothelial cellsInhibits signs of angiogenesis such as sprouting cells48
TnC from a cell lineHuman umbilical endothelial cellsBinds to α2β1 and αvβ3 integrins49
Large isoform of TnCRat and human VSMCUpregulates MMP-2 which cleaves TnC31
EGF-like TnC domainRat and human VSMCInduces apoptosis31
Recombinant A1A2 isoformRat VSMCPromotes VSMC chemotaxis (unlike other TnC isoforms)33
TnC isolated from a glioma cell lineAdult rat cardiomyocytesPromotes cardiomyocyte attachment to laminin34
TnC antisense oligonucleotideRat pulmonary arteries in organ culturePromotes VSMC apoptosis and upregulates osteopontin expression37
Human TnC from commercial company (Chemicon)Rat pulmonary artery VSMCsStimulates proliferation and survival via αVβ3 integrin20,44
TnC fragment containing Fn A–DHuman aortic VSMCReduces focal adhesion VSMC> endothelial cells21
Human aortic endothelial cells
TnC-deficient mouseMouse macrophagesBehaved as wild-type macrophages in response to TGFβ128
Human recombinant TnC (fibrinogen-like globe)Human macrophagesStimulated TNFα, IL-6, and IL-8 production51
TnC extracted from chick embryo brainsHuman polymorphonuclear leucocytes and monocytesInhibited chemotaxis via α5β1 integrin36
TnC from commercial company (Chemicon)Human monocyte-macrophagesStimulates MMP-9 secretion38
TnC from commercial company (Life Technologies)Mouse macrophage cell line (RAW264.7)Stimulates MMP-9 expression45
TnC from chick embryo fibroblast culturesHuman monocytes and T lymphocytesInhibited monocyte adhesion to fibronectin and T cell activation by alloantigens not anti-CD3 antibody50
TnC isolated from U251 glioma cell line and recombinant fragmentsHuman T lymphocytesTnFnIII A1A2 inhibits T cell activation35
Recombinant TnC fragmentsHuman T lymphocytesTnfnIII 1–5 inhibits αVβ1 and α4β1 mediated adhesion to fibronectin40
TnC isolated from U251 glioma cell line (Chemicon)Human T lymphocytesInhibited anti-CD3-induced cell proliferation41
Recombinant TnC fragmentsHuman T lymphocytesSupports tethering and rolling via binding to the terminal fibrinogen like domain of TnC in a parallel-plate flow chamber42
Plasmin cleaved TnCHuman T lymphocytesPlasmin cleavage of TnC converts it from a non-adhesive to an adhesive substrate for T cells43
TnC isolated from U251 glioma cell lineHuman plateletsPlatelets adhere to and are activated by TnC29
  • TnC, tenascin C; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor; MMP, matrix metalloproteinase; TGF, transforming growth factor; TNF, tumour necrosis factor; IL, interleukin; TnfnIII, tenascin C fibronectin type III repeat domain; VSMC, vascular smooth muscle cells.

5. Animal studies examining the expression and role of TnC in cardiovascular disease

The association of TnC with a range of cardiovascular pathologies has been examined in murine, lapine, porcine, bovine, and canine models of human cardiovascular diseases (Tables 35).5,10,15,17,21,23,33,34,5271 The most common pathology studied has been intimal hyperplasia (Table 3).5,15,23,33,5258 TnC has been implicated in the development of intimal hyperplasia following angioplasty, stenting, arteriotomy, and bypass grafting in animal species as diverse as mice and pigs.5,15,23,33,5258 TnC is expressed very rapidly following arterial injury in these models and its expression is reduced in situations where intimal hyperplasia is inhibited, such as prostaglandin E2 deficiency or treatment with a nitric oxide donor.5,58 Importantly, intimal hyperplasia has been reported to be reduced in two distinct mouse models of TnC deficiency, suggesting that this protein plays an active role in this pathology.52,53 Indeed in one study that employed arterial grafts placed in the carotid artery, a reduced proliferation of neointimal cells was demonstrated in TnC deficient by comparison to wild-type mice.52 This same research group reported a similar finding of reduced number and proliferation of neointimal cells after aortotomy in TnC-deficient mice.53

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Table 3

Association of TnC expression with intimal hyperplasia in animal models

Intimal hyperplasia model and speciesFindings at site of intimal hyperplasia
Wire femoral artery injury; mouseReduced intimal hyperplasia in PGE2 deficient mouse associated with reduced TnC mRNA expression5
Abdominal aorta-to-carotid artery interposition grafting; mouseReduced neointimal hyperplasia in TnC-deficient mice52
Longitudinal aortotomy; mouseTnC-deficient mice have reduced intimal hyperplasia53
Balloon aortic injury; ratIncreased TnC protein expression first within the media and later the neointima23
Arterial graft; ratTopical cilostazol inhibits intimal hyperplasia associated with decreased TnC protein expression15
Balloon carotid injury; ratIncreased AIA2 TnC isoform mRNA and protein expression associated with intimal hyperplasia33
Balloon carotid injury; ratTnC protein expression increased within the intima after balloon injury54
Balloon carotid injury; rat and pigIncreased TnC mRNA and protein expression in adventitial myofibroblasts early and intima late after injury55
Left coronary artery stenting; miniature pigTnC mRNA and protein expression associated with the severity of intimal hyperplasia56
Coronary artery angioplasty; pigUpregulation of TnC mRNA within 2 h of injury57
Jugular vein grafts implanted in carotid artery; hypercholesterolaemic rabbitTopical nitric oxide donor reduces intimal hyperplasia and TnC protein expression within graft58
  • TnC, tenascin C; PGE2, prostaglandin E2.

Studies in rodent, pig, and dog models of myocardial infarction have demonstrated that TnC is highly expressed from approximately day 1 to day 14 within the peri-infarct area. This has promoted interest in developing diagnostic aids that incorporate antibodies targeting this protein (Table 4).34,5964 The TnC expression has been linked to an exaggerated repair process after myocardial infarction with reduced interstitial fibrosis reported in TnC-deficient mice following coronary artery ligation.59 TnC-deficient mice also have reduced myocardial stiffness on echocardiography after myocardial infarction.59 TnC expression has also been positively linked to a range of other cardiovascular pathologies, including atherosclerosis, pulmonary artery hypertension, neovascularization, the peri-infarct repair process following stroke, angiotensin II-induced cardiac fibrosis, vasospasm following subarachnoid haemorrhage, and vascular calcification (Table 5).10,17,21,23,59,6571 In keeping with in vitro findings noted earlier, neovascularization has been reported to be reduced in TnC-deficient mice, suggesting TnC promotes angiogenesis.10

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Table 4

Association of TnC expression with post-myocardial infarction changes in animal models

Myocardial infarction model and speciesFindings
Coronary artery ligation; mouseTnC-deficient mice had less interstitial fibrosis in peri-infarct areas59
Temporary left coronary occlusion; mouseSmad 3-deficient mice had reduced myocardial TnC protein expression post-infarction60
Temporary left coronary occlusion; rat(125)I-labeled anti-TnC antibody uptake at 1–3 days after infarction; reduced by 7 days61
Left coronary ligation; rat111In anti-TnC antibody uptake increased days 1–5 following infarction62
Coronary artery ligation: ratTnC mRNA and protein expression in fibroblasts in the area of infarction within 24 h which disappears by 14 days involvement in the phases of MI healing34
Left anterior descending artery occlusion; pigMesenchymal stem cell injection association with cardiac TnC protein upregulation and increased cardiac nerve density (a possible source of arrhythmia)63
Temporary coronary occlusion; dogCardiac TnC protein upregulated64
  • TnC, tenascin C; MI, myocardial infarction.

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Table 5

Association of TnC expression with a range of cardiovascular pathologies in animal models

Cardiovascular pathologyModel and speciesFindings
AtherosclerosisApolipoprotein E deficient; mouseIncreased TnC protein expression in areas of atheroma23
AtherosclerosisApolipoprotein E deficient; mouseIncreased TnC protein staining in areas of atheroma and activated macrophages65
AtherosclerosisSpontaneously hypertensive; ratsAortic TnC protein staining increased with age, hypertension, and at branch points17,21
Pulmonary artery hypertensionChronic hypoxia-induced PAH; rat and calfCirculating monocyte/macrophage precursors contribute to production of TnC66
Pulmonary artery hypertensionMonocrotaline-induced PAH; ratUpregulation of pulmonary artery TnC protein associated with PAH; endothelin B deficiency promotes PAH and TnC protein expression67
Pulmonary artery hypertensionPulmonary artery ligation; pigIncreased pulmonary TnC mRNA and protein expression68
NeovascularizationBone marrow transplant plus intramyocardial PDGF injection; mouseDonor-derived cells recruited to the heart within 24 h of PDGF injection at sites of TnC protein expression10
NeovascularizationCardiac transplant; mouseTnC-deficient mice reduced neovascularization10
Cerebral infarctionMiddle cerebral artery occlusion; ratGenomic study of peri-infarct cortex showed upregulation of TnC mRNA69
Cardiac fibrosisAngiotensin II infusion; mouseCardiac fibrosis associated with increased TnC mRNA and protein expression59
Sub-arachnoid haemorrhageCisternal injection of blood; ratTnC protein staining increased at sites of artery vasospasm70
Vascular calcificationSubdermal injection of elastin; ratIncreased TnC protein staining along with MMPs at sites of calcification71
  • TnC, tenascin C; PAH, pulmonary artery hypertension; PDGF, platelet-derived growth factor; MMP, matrix metalloproteinase.

To summarize, studies in animal models most clearly support a role of TnC in intimal hyperplasia, although the exact mechanisms for this are unclear. Although TnC is associated with many other cardiovascular pathologies in animal models, clear evidence that links TnC with their development and outcomes is currently lacking.

6. Human studies examining the expression of TnC in relation to cardiovascular disease

A large number of studies have examined the expression of TnC in biopsies removed from patients with a variety of cardiac and other cardiovascular diseases (Tables 6 and 7).9,10,20,31,34,38,7284 TnC expression within athero-thrombosis has been associated with acute coronary syndrome.10,38,72 TnC staining was localized in areas of plaque rupture and macrophage infiltration. Similar to animal studies, TnC expression has also been localized within areas of intimal hyperplasia (at sites of coronary restenosis or in saphenous vein coronary artery bypass grafts), myocardial infarction, cardiomyopathy, and coronary valve calcification.34,38,7376 High tissue levels of TnC have also been reported within a range of other cardiovascular pathologies, including carotid atherosclerosis, pulmonary artery hypertension, abdominal aortic aneurysm, renal access graft intimal hyperplasia, renal transplant vasculopathy, and varicose veins.9,20,31,7784 In contrast to the large number of studies examining the expression of TnC in tissue biopsies, there have been fewer investigations of the association of circulating concentrations of TnC with cardiovascular disease.70,8591 The serum or plasma concentration of TnC has been reported to be increased in patients with a range of cardiac problems, including acute myocardial infarction, pulmonary thromboembolism, pulmonary artery hypertension, left ventricular hypertrophy, and dilated cardiomyopathy compared with controls in cross-sectional studies (Table 8).8591 Overall, the number of subjects included in these studies has been small, however, with a total of only 408 cases and 136 controls included in the independent cross-sectional studies identified in this systematic review (Table 8). The TnC isoform measured in these studies has varied but in most instances appears to have been the high molecular weight isoform containing the fibronectin type III C domain. Assays have been performed using commercial enzyme-linked immunoassays from two different companies.8789 The circulating TnC concentration has not only been reported to be increased in patients with cardiac disease but also related to specific clinical findings, imaging results, and subsequent outcomes in these patients.8793 Serum TnC concentration has, for example, been correlated with New York Heart Association functional class and left ventricular ejection fraction in patients with heart failure.88,90 Serum TnC has also been reported to predict the prospective incidence of cardiovascular events in patients who have recently had a myocardial infarction, have heart failure or chronic kidney disease.89,92,93 The reported area under the curves of receiver operator characteristic curves in these studies were between 0.77 and 0.79.89,93 These findings suggest that most likely serum TnC would need to be combined with other clinical and biomarker predictors to be of clinical value. In summary, data from human association studies fit with animal data linking TnC with a range of cardiovascular diseases, although the therapeutic and diagnostic value has been little examined.

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Table 6

Studies examining the expression of TnC in biopsies taken from patients with cardiac disease

Number of cases and controlsBiopsiesCasesControlsFindings
4Coronary artery thrombusAcute coronary syndromeNoneTnC expressed within coronary artery thrombus and co-localizes with EPC marker Tie-210
51Coronary atheromaAcute coronary syndromeStable anginaTnC staining area larger in atheroma from patients with ACS and correlated with thrombus, angiogenesis, intraplaque haemorrhage, and macrophage/lymphocyte infiltration72
15Coronary atheromaPatients having coronary bypass surgeryInternal thoracic artery from the same patientsTnC staining in areas of plaque rupture and correlated with macrophage infiltration38
20Right atrial auricleValvular heart diseaseStable coronary heart diseaseTnC expression increased in biopsies with more severe histological evidence of cardiac damage73
22Aortic and pulmonary valvesIschaemic or dilated cardiomyopathyPM cases with no history of cardiac diseaseCardiomyopathy cases increased TnC expression74
12Aortic valve cuspsValvular heart disease having valve replacementPM cases with no history of cardiac diseaseIncreased TnC in calcified valves75
43Coronary artery stenoses obtained by atherectomyRestenosis after coronary angioplastyPrimary coronary stenosesTnC expression increases transiently within 1 month of coronary angioplasty34
20Coronary bypass graftsHeart transplant recipientsSaphenous vein from patients undergoing coronary bypassTnC protein expressed within the adventitia and media of patent vein grafts but not within occluded vein grafts or non-arterialized control saphenous veins38
40Myocardial biopsiesMyocardial infarctionNormal myocardiumTnC expressed post MI up to 3 weeks after76
  • EPC, endothelial progenitor cells; ACS, acute coronary syndrome; TnC, tenascin C; PM, post-mortem; MI, myocardial infarction.

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Table 7

Studies examining the expression of TnC in biopsies taken from patients with a variety of cardiovascular diseases

Number of cases and controlsBiopsiesCasesControlsFindings
20Carotid atheroma and control ‘normal’ iliac arteryPatients undergoing carotid endarterectomyPatients having AAA repairStaining for TnfnIII marked in atherosclerotic plaques and particularly macrophage rich areas77
16Carotid atheromaPatients undergoing carotid endarterectomyNoneLarge (280 kDa) and small (220 kDa) TnC isoforms and 85 and 65 kDa EGF-like domain fragments detected31
10Long saphenous veinPatients undergoing varicose veins surgeryPatients undergoing coronary bypass surgeryUpregulation of TnC78
NSLong saphenous veinPatients undergoing varicose veins surgeryPatients undergoing coronary bypass surgeryIncreased intimal TnC expression79
18Pulmonary arteryFamilial pulmonary artery hypertensionNoneTnC highly expressed in all biopsies9
7Pulmonary arteryPulmonary artery hypertensionNoneTnC staining correlates with grade of pulmonary artery pathology (Heath-Edwards grading)20
17Infra-renal aortaPatients undergoing AAA repairOrgan donorsTnC upregulated in AAA80
23Infra-renal aortaPatients undergoing AAA repairPatients undergoing aortic bypass for occlusive diseaseIncreased staining for TnC in AAA samples association with adventitial inflammation and neovascularization81
15Thoracic aortic biopsiesMarfan syndrome and bicuspid aortic valve undergoing thoracic aortic aneurysm repairNSReduced TnC expression by VSMCs from aneurysm biopsies82
12Graft stenosesFailed PTFE loop arterio-venous graftsNoneTnC staining marked in luminal layer of intimal hyperplasia at the site of cell proliferation based on proliferating cell nuclear antigen expression83
10Renal arteriesFailed kidney transplantsNoneIncreased TnC expression observed in media early in rejection process84
  • EGF, epidermal growth factor; TnC, tenascin C; AAA, abdominal aortic aneurysm; VSMC, vascular smooth muscle cells; PTFE, polytetraflurorethylene; NS, not stated.

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Table 8

Case–control studies examining the association of circulating TnC concentrations with cardiac disease

CasesControlsSampleOther findings
DiagnosisNTnC (ng/mL)NTnC (ng/mL)
Pulmonary thromboembolism8534120 ± 38*Healthy volunteers2016 ± 3Plasma
Pulmonary artery hypertension8636111 ± 13*Age- and gender-matched healthy volunteers4444 ± 2PlasmaAUC of ROC curve 0.87
Hypertensive heart disease87951000 (700–1200)**,a,bHealthy volunteers12500 (400–600)aSerumTnFNIIIB higher in subjects with eccentric compared to concentric LV hypertrophy
Dilated cardiomyopathy8810773 ± 35*Healthy volunteers2031 ± 9SerumTnC correlated with NYHA functional class and LV echographic parameters
Acute myocardial infarction (day 5)8910583 ± 43*Healthy volunteers2027 ± 12SerumPeak TnC predicted increase in LV end-diastolic volume and MACE during follow-up
Dilated cardiomyopathy903169 ± 33*Age- and gender-matched healthy volunteers2040 ± 14SerumTnC correlated with NYHA functional class and LV echographic parameters
Hypertensive heart disease916460 ± 40Patients responding to CRT4647 ± 30*SerumTnC dropped in 72% of treated patients at 6 month follow-up
  • Comparisons of TnC between cases and controls: *P < 0.01; **P < 0.05. Shown are mean and standard deviation except superscript ‘a’ where median and inter-quartile range are shown.

  • bIn this study, the lower molecular weight FNIIIB domain containing TnC isoform was measured while in other studies the higher molecular weight FNIIIC domain containing TnC isoform appears to have been measured. TnC, tenascin C; AUC, area under the curve; ROC, receiver operator characteristic; LV, left ventricular; NYHA, New York Heart Association; MACE, major adverse cardiovascular events; CRT, cardiac resynchronization therapy.

7. Association of genetic polymorphisms in the gene encoding TnC and cardiovascular disease

TnC is encoded by a large gene composed of 28 exons spanning nearly 100 kb on Chromosome 9 (NCBI Nucleotide database Ref Seq NC_000009). Its transcription is directed by a single promoter and regulated by both positive and negative elements located in the first untranslated exon,94 which is separated from the translation initiation site in exon 2 by a large intron of approximately 18 kb.95 There are 1167 polymorphisms located in and around the gene, 67 of which affect the coding region (NCBI dbSNP); however, their functional consequences and association with cardiovascular disease have not been thoroughly investigated. It is tempting to speculate that inheritance of particular polymorphic variants could influence expression levels of TnC and account for some of the individual variation in risk of cardiovascular disease. A genome-wide association study of genes for biomarkers of cardiovascular disease identified rs17819305, located in intron 15 of the TnC gene, as being associated with gammaglutamyl transferase levels in 1955 hypertensive subjects.96 Otherwise, there has only been a single published study specifically examining the association of genetic polymorphisms in TNC and cardiovascular disease, and this did not include rs17819305.97 Minear et al.97 genotyped a total of 35 single nucleotide polymorphisms (SNPs), including 21 haplotype tagging SNPs, in a range of subjects that had been assessed for different measures of atherosclerosis. The subjects examined included 205 heart transplant donors who had provided ascending aortic samples; 1325 patients who had undergone coronary angiography to assess severity of coronary atherosclerosis; and 879 families with a history of coronary heart disease. Three SNPs, rs3789875, rs12347433, and rs4552883, representing a block of linkage disequilibrium were significantly associated with aortic atherosclerosis plaque presence in the heart transplant donors and coronary heart disease in the two large subject groups. One of these SNPs, rs12347433, is a synonymous polymorphism causing a change in the mRNA without affecting the amino acid sequence of the TnC protein. This type of synonymous polymorphism has been suggested to alter mRNA function or stability which could alter translation and thus TnC expression. However, none of these SNPs was associated with TnC expression measured by microarrays within the 104 patients in which aortic RNA was available, suggesting these polymorphisms may be acting via mechanisms unrelated to aortic concentration of TnC mRNA.

8. Summary and future directions

A large number of studies suggest that TnC is transiently expressed in association with a range of cardiovascular diseases in both animal models and patients. Whether this association is part of the repair process or pathological is not completely resolved in most instances. Studies from TnC-deficient mice suggest that in the case of intimal hyperplasia (perhaps the best-studied example) that TnC plays a pathological role, most likely because of the ability of TnC to promote MMP production, and VSMC proliferation and chemotaxis.20,34,37,44,52,53 The role of TnC in atherosclerosis is less clear cut, although a number of findings (such as its expression at sites of plaque rupture, its involvement in neovascularization, and its ability to influence VSMC phenotype and pro-inflammatory cytokine/MMP production) would suggest that it may play a role in promoting the development and complications of this pathology.10,36,38,45,51,72 We identified no studies examining TnC deficiency, overexpression, or inhibition on atherosclerosis progression in animal models. Studies of this type are required to provide further insight on the role of this extracellular matrix protein in cardiovascular disease. The rapid upregulation of TnC following ischaemia events, such as myocardial infarction, suggests the possibility of targeting TnC as a diagnostic or prognostic aid in patients with cardiovascular disease, e.g. as a circulating or tissue biomarker.76,89 Further studies in larger populations are, however, required to assess the feasibility and clinical value of such an approach.

Conflict of interest: none declared.

Funding

This work was supported by the National Health and Medical Research Council and the Office of Health and Medical Research, Australia.

References

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