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.

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.1–3 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.

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.1–3 TnC polypeptides are made up of a number of domains (Figure 1A) and include: 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.

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

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

  • A series of fibronectin type III domains;

  • A distal globular fibrinogen-homology domain.

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.

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.

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.

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).5–26 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.11,18–20 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

Table 1

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

Upregulators of TnC Cell type studied TnC form induced 
Prostaglandin E2 Mouse VSMCs5 mRNA 
LPS and other TLR ligands Monocyte-derived cells such as macrophages6 mRNA and protein 
Wnt pathway Mouse pulmonary artery VSMCs7 mRNA and protein 
CD137 ligation RAW264.7 (murine myeloid cell line)8 mRNA 
ERK 1/2 mitogen-activated protein kinases Human pulmonary artery VSMCs9 mRNA and protein 
RhoA and Rho kinase ROCK Rat pulmonary artery endothelial cells10,11 mRNA 
Interleukin-4 Human peripheral blood-derived macrophages12 mRNA 
Cyclic stretch Human aortic VSMCs mRNA and protein 
Rat aortic VSMCs13,14 
Platelet-derived growth factor Rat aortic VSMC15–17 mRNA and protein including three isoforms (210, 220, and 250 kDa) 
Prx1 (homeobox transcription factor) VSMC cell line18 mRNA 
Denatured collagen (via β3 integrin and ERK 1/2) VSMC cell line19,20 mRNA and protein 
Angiotensin II Human aortic VSMC mRNA and protein 
Rat aortic VSMC 
Human aortic endothelial cells16,17,21,22 
Transforming growth factor beta Human aortic VSMC mRNA and protein 
Rat aortic VSMC 
Human aortic endothelial cells17,21 
Downregulators of TnC Cell type studied TnC form downregulated 

 
Shear stress mimicking atheroprone flow Human iliac vein endothelial and VSMC co-culture23 mRNA 
Dexamethasone Human peripheral blood-derived macrophages12 mRNA 
Cilostazol Rat aortic VSMC15 mRNA 
Glafenine hydrochloride (NSAID) Human aortic VSMCs24 Protein 
9-cis retinoid acid Human aortic VSMCs25 Protein 
Polymerized (compared to monomer) type 1 collagen Human umbilical artery VSMCs26 mRNA 
Upregulators of TnC Cell type studied TnC form induced 
Prostaglandin E2 Mouse VSMCs5 mRNA 
LPS and other TLR ligands Monocyte-derived cells such as macrophages6 mRNA and protein 
Wnt pathway Mouse pulmonary artery VSMCs7 mRNA and protein 
CD137 ligation RAW264.7 (murine myeloid cell line)8 mRNA 
ERK 1/2 mitogen-activated protein kinases Human pulmonary artery VSMCs9 mRNA and protein 
RhoA and Rho kinase ROCK Rat pulmonary artery endothelial cells10,11 mRNA 
Interleukin-4 Human peripheral blood-derived macrophages12 mRNA 
Cyclic stretch Human aortic VSMCs mRNA and protein 
Rat aortic VSMCs13,14 
Platelet-derived growth factor Rat aortic VSMC15–17 mRNA and protein including three isoforms (210, 220, and 250 kDa) 
Prx1 (homeobox transcription factor) VSMC cell line18 mRNA 
Denatured collagen (via β3 integrin and ERK 1/2) VSMC cell line19,20 mRNA and protein 
Angiotensin II Human aortic VSMC mRNA and protein 
Rat aortic VSMC 
Human aortic endothelial cells16,17,21,22 
Transforming growth factor beta Human aortic VSMC mRNA and protein 
Rat aortic VSMC 
Human aortic endothelial cells17,21 
Downregulators of TnC Cell type studied TnC form downregulated 

 
Shear stress mimicking atheroprone flow Human iliac vein endothelial and VSMC co-culture23 mRNA 
Dexamethasone Human peripheral blood-derived macrophages12 mRNA 
Cilostazol Rat aortic VSMC15 mRNA 
Glafenine hydrochloride (NSAID) Human aortic VSMCs24 Protein 
9-cis retinoid acid Human aortic VSMCs25 Protein 
Polymerized (compared to monomer) type 1 collagen Human umbilical artery VSMCs26 mRNA 

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).10,20,21,28–50 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

Table 2

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

TnC form or intervention Cell type Effects 
TnC fragment (A2 isoform) Human dermal microvascular endothelial cells Proliferation inhibited30 
TnC from commercial company (Chemicon) Rat cardiac microvascular endothelial cells Promotes response to angiogenic signals, such as PDGF and VEGF10 
TnC from commercial company (Chemicon) Bovine and human retinal endothelial cells Promotes endothelial cell tube formation and branching32 
Recombinant chick TnC Bovine aortic endothelial cells Stimulates actin cytoskeletal reorganization typical of sprouting endothelial cells39 
Large and small splice variants of TnC Bovine aortic endothelial cells TnC fragment containing Fn A-D induces loss of focal adhesion by binding annexin II46,47 
TnC blocking antibody Bovine aortic endothelial cells Inhibits signs of angiogenesis such as sprouting cells48 
TnC from a cell line Human umbilical endothelial cells Binds to α2β1 and αvβ3 integrins49 
Large isoform of TnC Rat and human VSMC Upregulates MMP-2 which cleaves TnC31 
EGF-like TnC domain Rat and human VSMC Induces apoptosis31 
Recombinant A1A2 isoform Rat VSMC Promotes VSMC chemotaxis (unlike other TnC isoforms)33 
TnC isolated from a glioma cell line Adult rat cardiomyocytes Promotes cardiomyocyte attachment to laminin34 
TnC antisense oligonucleotide Rat pulmonary arteries in organ culture Promotes VSMC apoptosis and upregulates osteopontin expression37 
Human TnC from commercial company (Chemicon) Rat pulmonary artery VSMCs Stimulates proliferation and survival via αVβ3 integrin20,44 
TnC fragment containing Fn A–D Human aortic VSMC Reduces focal adhesion VSMC> endothelial cells21 
Human aortic endothelial cells 
TnC-deficient mouse Mouse macrophages Behaved as wild-type macrophages in response to TGFβ128 
Human recombinant TnC (fibrinogen-like globe) Human macrophages Stimulated TNFα, IL-6, and IL-8 production51 
TnC extracted from chick embryo brains Human polymorphonuclear leucocytes and monocytes Inhibited chemotaxis via α5β1 integrin36 
TnC from commercial company (Chemicon) Human monocyte-macrophages Stimulates MMP-9 secretion38 
TnC from commercial company (Life Technologies) Mouse macrophage cell line (RAW264.7) Stimulates MMP-9 expression45 
TnC from chick embryo fibroblast cultures Human monocytes and T lymphocytes Inhibited monocyte adhesion to fibronectin and T cell activation by alloantigens not anti-CD3 antibody50 
TnC isolated from U251 glioma cell line and recombinant fragments Human T lymphocytes TnFnIII A1A2 inhibits T cell activation35 
Recombinant TnC fragments Human T lymphocytes TnfnIII 1–5 inhibits αVβ1 and α4β1 mediated adhesion to fibronectin40 
TnC isolated from U251 glioma cell line (Chemicon) Human T lymphocytes Inhibited anti-CD3-induced cell proliferation41 
Recombinant TnC fragments Human T lymphocytes Supports tethering and rolling via binding to the terminal fibrinogen like domain of TnC in a parallel-plate flow chamber42 
Plasmin cleaved TnC Human T lymphocytes Plasmin cleavage of TnC converts it from a non-adhesive to an adhesive substrate for T cells43 
TnC isolated from U251 glioma cell line Human platelets Platelets adhere to and are activated by TnC29 
TnC form or intervention Cell type Effects 
TnC fragment (A2 isoform) Human dermal microvascular endothelial cells Proliferation inhibited30 
TnC from commercial company (Chemicon) Rat cardiac microvascular endothelial cells Promotes response to angiogenic signals, such as PDGF and VEGF10 
TnC from commercial company (Chemicon) Bovine and human retinal endothelial cells Promotes endothelial cell tube formation and branching32 
Recombinant chick TnC Bovine aortic endothelial cells Stimulates actin cytoskeletal reorganization typical of sprouting endothelial cells39 
Large and small splice variants of TnC Bovine aortic endothelial cells TnC fragment containing Fn A-D induces loss of focal adhesion by binding annexin II46,47 
TnC blocking antibody Bovine aortic endothelial cells Inhibits signs of angiogenesis such as sprouting cells48 
TnC from a cell line Human umbilical endothelial cells Binds to α2β1 and αvβ3 integrins49 
Large isoform of TnC Rat and human VSMC Upregulates MMP-2 which cleaves TnC31 
EGF-like TnC domain Rat and human VSMC Induces apoptosis31 
Recombinant A1A2 isoform Rat VSMC Promotes VSMC chemotaxis (unlike other TnC isoforms)33 
TnC isolated from a glioma cell line Adult rat cardiomyocytes Promotes cardiomyocyte attachment to laminin34 
TnC antisense oligonucleotide Rat pulmonary arteries in organ culture Promotes VSMC apoptosis and upregulates osteopontin expression37 
Human TnC from commercial company (Chemicon) Rat pulmonary artery VSMCs Stimulates proliferation and survival via αVβ3 integrin20,44 
TnC fragment containing Fn A–D Human aortic VSMC Reduces focal adhesion VSMC> endothelial cells21 
Human aortic endothelial cells 
TnC-deficient mouse Mouse macrophages Behaved as wild-type macrophages in response to TGFβ128 
Human recombinant TnC (fibrinogen-like globe) Human macrophages Stimulated TNFα, IL-6, and IL-8 production51 
TnC extracted from chick embryo brains Human polymorphonuclear leucocytes and monocytes Inhibited chemotaxis via α5β1 integrin36 
TnC from commercial company (Chemicon) Human monocyte-macrophages Stimulates MMP-9 secretion38 
TnC from commercial company (Life Technologies) Mouse macrophage cell line (RAW264.7) Stimulates MMP-9 expression45 
TnC from chick embryo fibroblast cultures Human monocytes and T lymphocytes Inhibited monocyte adhesion to fibronectin and T cell activation by alloantigens not anti-CD3 antibody50 
TnC isolated from U251 glioma cell line and recombinant fragments Human T lymphocytes TnFnIII A1A2 inhibits T cell activation35 
Recombinant TnC fragments Human T lymphocytes TnfnIII 1–5 inhibits αVβ1 and α4β1 mediated adhesion to fibronectin40 
TnC isolated from U251 glioma cell line (Chemicon) Human T lymphocytes Inhibited anti-CD3-induced cell proliferation41 
Recombinant TnC fragments Human T lymphocytes Supports tethering and rolling via binding to the terminal fibrinogen like domain of TnC in a parallel-plate flow chamber42 
Plasmin cleaved TnC Human T lymphocytes Plasmin cleavage of TnC converts it from a non-adhesive to an adhesive substrate for T cells43 
TnC isolated from U251 glioma cell line Human platelets Platelets 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.

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 3–5).5,10,15,17,21,23,33,34,52–71 The most common pathology studied has been intimal hyperplasia (Table 3).5,15,23,33,52–58 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.5,15,23,33,52–58 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

Table 3

Association of TnC expression with intimal hyperplasia in animal models

Intimal hyperplasia model and species Findings at site of intimal hyperplasia 
Wire femoral artery injury; mouse Reduced intimal hyperplasia in PGE2 deficient mouse associated with reduced TnC mRNA expression5 
Abdominal aorta-to-carotid artery interposition grafting; mouse Reduced neointimal hyperplasia in TnC-deficient mice52 
Longitudinal aortotomy; mouse TnC-deficient mice have reduced intimal hyperplasia53 
Balloon aortic injury; rat Increased TnC protein expression first within the media and later the neointima23 
Arterial graft; rat Topical cilostazol inhibits intimal hyperplasia associated with decreased TnC protein expression15 
Balloon carotid injury; rat Increased AIA2 TnC isoform mRNA and protein expression associated with intimal hyperplasia33 
Balloon carotid injury; rat TnC protein expression increased within the intima after balloon injury54 
Balloon carotid injury; rat and pig Increased TnC mRNA and protein expression in adventitial myofibroblasts early and intima late after injury55 
Left coronary artery stenting; miniature pig TnC mRNA and protein expression associated with the severity of intimal hyperplasia56 
Coronary artery angioplasty; pig Upregulation of TnC mRNA within 2 h of injury57 
Jugular vein grafts implanted in carotid artery; hypercholesterolaemic rabbit Topical nitric oxide donor reduces intimal hyperplasia and TnC protein expression within graft58 
Intimal hyperplasia model and species Findings at site of intimal hyperplasia 
Wire femoral artery injury; mouse Reduced intimal hyperplasia in PGE2 deficient mouse associated with reduced TnC mRNA expression5 
Abdominal aorta-to-carotid artery interposition grafting; mouse Reduced neointimal hyperplasia in TnC-deficient mice52 
Longitudinal aortotomy; mouse TnC-deficient mice have reduced intimal hyperplasia53 
Balloon aortic injury; rat Increased TnC protein expression first within the media and later the neointima23 
Arterial graft; rat Topical cilostazol inhibits intimal hyperplasia associated with decreased TnC protein expression15 
Balloon carotid injury; rat Increased AIA2 TnC isoform mRNA and protein expression associated with intimal hyperplasia33 
Balloon carotid injury; rat TnC protein expression increased within the intima after balloon injury54 
Balloon carotid injury; rat and pig Increased TnC mRNA and protein expression in adventitial myofibroblasts early and intima late after injury55 
Left coronary artery stenting; miniature pig TnC mRNA and protein expression associated with the severity of intimal hyperplasia56 
Coronary artery angioplasty; pig Upregulation of TnC mRNA within 2 h of injury57 
Jugular vein grafts implanted in carotid artery; hypercholesterolaemic rabbit Topical 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).34,59–64 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).10,17,21,23,59,65–71 In keeping with in vitro findings noted earlier, neovascularization has been reported to be reduced in TnC-deficient mice, suggesting TnC promotes angiogenesis.10

Table 4

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

Myocardial infarction model and species Findings 
Coronary artery ligation; mouse TnC-deficient mice had less interstitial fibrosis in peri-infarct areas59 
Temporary left coronary occlusion; mouse Smad 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; rat 111In anti-TnC antibody uptake increased days 1–5 following infarction62 
Coronary artery ligation: rat TnC 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; pig Mesenchymal stem cell injection association with cardiac TnC protein upregulation and increased cardiac nerve density (a possible source of arrhythmia)63 
Temporary coronary occlusion; dog Cardiac TnC protein upregulated64 
Myocardial infarction model and species Findings 
Coronary artery ligation; mouse TnC-deficient mice had less interstitial fibrosis in peri-infarct areas59 
Temporary left coronary occlusion; mouse Smad 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; rat 111In anti-TnC antibody uptake increased days 1–5 following infarction62 
Coronary artery ligation: rat TnC 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; pig Mesenchymal stem cell injection association with cardiac TnC protein upregulation and increased cardiac nerve density (a possible source of arrhythmia)63 
Temporary coronary occlusion; dog Cardiac TnC protein upregulated64 

TnC, tenascin C; MI, myocardial infarction.

Table 5

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

Cardiovascular pathology Model and species Findings 
Atherosclerosis Apolipoprotein E deficient; mouse Increased TnC protein expression in areas of atheroma23 
Atherosclerosis Apolipoprotein E deficient; mouse Increased TnC protein staining in areas of atheroma and activated macrophages65 
Atherosclerosis Spontaneously hypertensive; rats Aortic TnC protein staining increased with age, hypertension, and at branch points17,21 
Pulmonary artery hypertension Chronic hypoxia-induced PAH; rat and calf Circulating monocyte/macrophage precursors contribute to production of TnC66 
Pulmonary artery hypertension Monocrotaline-induced PAH; rat Upregulation of pulmonary artery TnC protein associated with PAH; endothelin B deficiency promotes PAH and TnC protein expression67 
Pulmonary artery hypertension Pulmonary artery ligation; pig Increased pulmonary TnC mRNA and protein expression68 
Neovascularization Bone marrow transplant plus intramyocardial PDGF injection; mouse Donor-derived cells recruited to the heart within 24 h of PDGF injection at sites of TnC protein expression10 
Neovascularization Cardiac transplant; mouse TnC-deficient mice reduced neovascularization10 
Cerebral infarction Middle cerebral artery occlusion; rat Genomic study of peri-infarct cortex showed upregulation of TnC mRNA69 
Cardiac fibrosis Angiotensin II infusion; mouse Cardiac fibrosis associated with increased TnC mRNA and protein expression59 
Sub-arachnoid haemorrhage Cisternal injection of blood; rat TnC protein staining increased at sites of artery vasospasm70 
Vascular calcification Subdermal injection of elastin; rat Increased TnC protein staining along with MMPs at sites of calcification71 
Cardiovascular pathology Model and species Findings 
Atherosclerosis Apolipoprotein E deficient; mouse Increased TnC protein expression in areas of atheroma23 
Atherosclerosis Apolipoprotein E deficient; mouse Increased TnC protein staining in areas of atheroma and activated macrophages65 
Atherosclerosis Spontaneously hypertensive; rats Aortic TnC protein staining increased with age, hypertension, and at branch points17,21 
Pulmonary artery hypertension Chronic hypoxia-induced PAH; rat and calf Circulating monocyte/macrophage precursors contribute to production of TnC66 
Pulmonary artery hypertension Monocrotaline-induced PAH; rat Upregulation of pulmonary artery TnC protein associated with PAH; endothelin B deficiency promotes PAH and TnC protein expression67 
Pulmonary artery hypertension Pulmonary artery ligation; pig Increased pulmonary TnC mRNA and protein expression68 
Neovascularization Bone marrow transplant plus intramyocardial PDGF injection; mouse Donor-derived cells recruited to the heart within 24 h of PDGF injection at sites of TnC protein expression10 
Neovascularization Cardiac transplant; mouse TnC-deficient mice reduced neovascularization10 
Cerebral infarction Middle cerebral artery occlusion; rat Genomic study of peri-infarct cortex showed upregulation of TnC mRNA69 
Cardiac fibrosis Angiotensin II infusion; mouse Cardiac fibrosis associated with increased TnC mRNA and protein expression59 
Sub-arachnoid haemorrhage Cisternal injection of blood; rat TnC protein staining increased at sites of artery vasospasm70 
Vascular calcification Subdermal injection of elastin; rat Increased 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.

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).9,10,20,31,34,38,72–84 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.34,38,73–76 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.9,20,31,77–84 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.70,85–91 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).85–91 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.87–89 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.87–93 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.

Table 6

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

Number of cases and controls Biopsies Cases Controls Findings 
Coronary artery thrombus Acute coronary syndrome None TnC expressed within coronary artery thrombus and co-localizes with EPC marker Tie-210 
51 Coronary atheroma Acute coronary syndrome Stable angina TnC staining area larger in atheroma from patients with ACS and correlated with thrombus, angiogenesis, intraplaque haemorrhage, and macrophage/lymphocyte infiltration72 
15 Coronary atheroma Patients having coronary bypass surgery Internal thoracic artery from the same patients TnC staining in areas of plaque rupture and correlated with macrophage infiltration38 
20 Right atrial auricle Valvular heart disease Stable coronary heart disease TnC expression increased in biopsies with more severe histological evidence of cardiac damage73 
22 Aortic and pulmonary valves Ischaemic or dilated cardiomyopathy PM cases with no history of cardiac disease Cardiomyopathy cases increased TnC expression74 
12 Aortic valve cusps Valvular heart disease having valve replacement PM cases with no history of cardiac disease Increased TnC in calcified valves75 
43 Coronary artery stenoses obtained by atherectomy Restenosis after coronary angioplasty Primary coronary stenoses TnC expression increases transiently within 1 month of coronary angioplasty34 
20 Coronary bypass grafts Heart transplant recipients Saphenous vein from patients undergoing coronary bypass TnC protein expressed within the adventitia and media of patent vein grafts but not within occluded vein grafts or non-arterialized control saphenous veins38 
40 Myocardial biopsies Myocardial infarction Normal myocardium TnC expressed post MI up to 3 weeks after76 
Number of cases and controls Biopsies Cases Controls Findings 
Coronary artery thrombus Acute coronary syndrome None TnC expressed within coronary artery thrombus and co-localizes with EPC marker Tie-210 
51 Coronary atheroma Acute coronary syndrome Stable angina TnC staining area larger in atheroma from patients with ACS and correlated with thrombus, angiogenesis, intraplaque haemorrhage, and macrophage/lymphocyte infiltration72 
15 Coronary atheroma Patients having coronary bypass surgery Internal thoracic artery from the same patients TnC staining in areas of plaque rupture and correlated with macrophage infiltration38 
20 Right atrial auricle Valvular heart disease Stable coronary heart disease TnC expression increased in biopsies with more severe histological evidence of cardiac damage73 
22 Aortic and pulmonary valves Ischaemic or dilated cardiomyopathy PM cases with no history of cardiac disease Cardiomyopathy cases increased TnC expression74 
12 Aortic valve cusps Valvular heart disease having valve replacement PM cases with no history of cardiac disease Increased TnC in calcified valves75 
43 Coronary artery stenoses obtained by atherectomy Restenosis after coronary angioplasty Primary coronary stenoses TnC expression increases transiently within 1 month of coronary angioplasty34 
20 Coronary bypass grafts Heart transplant recipients Saphenous vein from patients undergoing coronary bypass TnC protein expressed within the adventitia and media of patent vein grafts but not within occluded vein grafts or non-arterialized control saphenous veins38 
40 Myocardial biopsies Myocardial infarction Normal myocardium TnC 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.

Table 7

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

Number of cases and controls Biopsies Cases Controls Findings 
20 Carotid atheroma and control ‘normal’ iliac artery Patients undergoing carotid endarterectomy Patients having AAA repair Staining for TnfnIII marked in atherosclerotic plaques and particularly macrophage rich areas77 
16 Carotid atheroma Patients undergoing carotid endarterectomy None Large (280 kDa) and small (220 kDa) TnC isoforms and 85 and 65 kDa EGF-like domain fragments detected31 
10 Long saphenous vein Patients undergoing varicose veins surgery Patients undergoing coronary bypass surgery Upregulation of TnC78 
NS Long saphenous vein Patients undergoing varicose veins surgery Patients undergoing coronary bypass surgery Increased intimal TnC expression79 
18 Pulmonary artery Familial pulmonary artery hypertension None TnC highly expressed in all biopsies9 
Pulmonary artery Pulmonary artery hypertension None TnC staining correlates with grade of pulmonary artery pathology (Heath-Edwards grading)20 
17 Infra-renal aorta Patients undergoing AAA repair Organ donors TnC upregulated in AAA80 
23 Infra-renal aorta Patients undergoing AAA repair Patients undergoing aortic bypass for occlusive disease Increased staining for TnC in AAA samples association with adventitial inflammation and neovascularization81 
15 Thoracic aortic biopsies Marfan syndrome and bicuspid aortic valve undergoing thoracic aortic aneurysm repair NS Reduced TnC expression by VSMCs from aneurysm biopsies82 
12 Graft stenoses Failed PTFE loop arterio-venous grafts None TnC staining marked in luminal layer of intimal hyperplasia at the site of cell proliferation based on proliferating cell nuclear antigen expression83 
10 Renal arteries Failed kidney transplants None Increased TnC expression observed in media early in rejection process84 
Number of cases and controls Biopsies Cases Controls Findings 
20 Carotid atheroma and control ‘normal’ iliac artery Patients undergoing carotid endarterectomy Patients having AAA repair Staining for TnfnIII marked in atherosclerotic plaques and particularly macrophage rich areas77 
16 Carotid atheroma Patients undergoing carotid endarterectomy None Large (280 kDa) and small (220 kDa) TnC isoforms and 85 and 65 kDa EGF-like domain fragments detected31 
10 Long saphenous vein Patients undergoing varicose veins surgery Patients undergoing coronary bypass surgery Upregulation of TnC78 
NS Long saphenous vein Patients undergoing varicose veins surgery Patients undergoing coronary bypass surgery Increased intimal TnC expression79 
18 Pulmonary artery Familial pulmonary artery hypertension None TnC highly expressed in all biopsies9 
Pulmonary artery Pulmonary artery hypertension None TnC staining correlates with grade of pulmonary artery pathology (Heath-Edwards grading)20 
17 Infra-renal aorta Patients undergoing AAA repair Organ donors TnC upregulated in AAA80 
23 Infra-renal aorta Patients undergoing AAA repair Patients undergoing aortic bypass for occlusive disease Increased staining for TnC in AAA samples association with adventitial inflammation and neovascularization81 
15 Thoracic aortic biopsies Marfan syndrome and bicuspid aortic valve undergoing thoracic aortic aneurysm repair NS Reduced TnC expression by VSMCs from aneurysm biopsies82 
12 Graft stenoses Failed PTFE loop arterio-venous grafts None TnC staining marked in luminal layer of intimal hyperplasia at the site of cell proliferation based on proliferating cell nuclear antigen expression83 
10 Renal arteries Failed kidney transplants None Increased 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.

Table 8

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

Cases
 
Controls
 
Sample Other findings 
Diagnosis N TnC (ng/mL)  N TnC (ng/mL)   
Pulmonary thromboembolism85 34 120 ± 38* Healthy volunteers 20 16 ± 3 Plasma  
Pulmonary artery hypertension86 36 111 ± 13* Age- and gender-matched healthy volunteers 44 44 ± 2 Plasma AUC of ROC curve 0.87 
Hypertensive heart disease87 95 1000 (700–1200)**,a,b Healthy volunteers 12 500 (400–600)a Serum TnFNIIIB higher in subjects with eccentric compared to concentric LV hypertrophy 
Dilated cardiomyopathy88 107 73 ± 35* Healthy volunteers 20 31 ± 9 Serum TnC correlated with NYHA functional class and LV echographic parameters 
Acute myocardial infarction (day 5)89 105 83 ± 43* Healthy volunteers 20 27 ± 12 Serum Peak TnC predicted increase in LV end-diastolic volume and MACE during follow-up 
Dilated cardiomyopathy90 31 69 ± 33* Age- and gender-matched healthy volunteers 20 40 ± 14 Serum TnC correlated with NYHA functional class and LV echographic parameters 
Hypertensive heart disease91 64 60 ± 40 Patients responding to CRT 46 47 ± 30* Serum TnC dropped in 72% of treated patients at 6 month follow-up 
Cases
 
Controls
 
Sample Other findings 
Diagnosis N TnC (ng/mL)  N TnC (ng/mL)   
Pulmonary thromboembolism85 34 120 ± 38* Healthy volunteers 20 16 ± 3 Plasma  
Pulmonary artery hypertension86 36 111 ± 13* Age- and gender-matched healthy volunteers 44 44 ± 2 Plasma AUC of ROC curve 0.87 
Hypertensive heart disease87 95 1000 (700–1200)**,a,b Healthy volunteers 12 500 (400–600)a Serum TnFNIIIB higher in subjects with eccentric compared to concentric LV hypertrophy 
Dilated cardiomyopathy88 107 73 ± 35* Healthy volunteers 20 31 ± 9 Serum TnC correlated with NYHA functional class and LV echographic parameters 
Acute myocardial infarction (day 5)89 105 83 ± 43* Healthy volunteers 20 27 ± 12 Serum Peak TnC predicted increase in LV end-diastolic volume and MACE during follow-up 
Dilated cardiomyopathy90 31 69 ± 33* Age- and gender-matched healthy volunteers 20 40 ± 14 Serum TnC correlated with NYHA functional class and LV echographic parameters 
Hypertensive heart disease91 64 60 ± 40 Patients responding to CRT 46 47 ± 30* Serum TnC 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.

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.

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.

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