Tenascin-C promotes chronic pressure overload-induced cardiac dysfunction, hypertrophy and myocardial fibrosis

Podesser, Bruno K.; Kreibich, Maximilian; Dzilic, Elda; Santer, David; Förster, Lorenz; Trojanek, S; Abraham, Dietmar; Krššák, Martin; Klein, Klaus Ulrich; Tretter, Eva Verena; Kaun, Christoph; Wojta, Johann; Kapeller, Barbara; Gonçalves, Inês Fonseca; Trescher, Karola; Kiss, Attila

doi:10.1097/hjh.0000000000001628

Cited by 42 publications

(37 citation statements)

References 45 publications

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“…This was accompanied by reduced LV and myocyte hypertrophy, less interstitial fibrosis, and reduced expression of matrix metalloproteinase (MMP)-2 and MMP-9 expression. 6 More recently, our group demonstrated that TN-C mRNA is up-regulated after MI in the border and infarcted zones, accompanied with a significant increase of plasma TN-C in a rat model of MI. 7 In line with that, Imanaka-Yoshida et al 8 described that ischaemia induced mRNA expression of TN-C within 24 h, which peaks on Day 5 and ultimately diminishes around Day 14.…”

Section: Introductionmentioning

confidence: 91%

Tenascin‐C aggravates ventricular dilatation and angiotensin‐converting enzyme activity after myocardial infarction in mice

et al. 2020

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Aims Tenascin-C (TN-C) is suggested to be detrimental in cardiac remodelling after myocardial infarction (MI). The aim of this study is to reveal the effects of TN-C on extracellular matrix organization and its haemodynamic influence in an experimental mouse model of MI and in myocardial cell culture during hypoxic conditions. Methods and results Myocardial infarction was induced in TN-C knockout (TN-C KO) and wild-type mice. Six weeks later, cardiac function was studied by magnetic resonance imaging and under isolated working heart conditions. Myocardial mRNA levels and immunoreactivity of TN-C, TIMP-1, TIMP-3, and matrix metalloproteinase (MMP)-9, as well as serum and tissue activities of angiotensin-converting enzyme (ACE), were determined at 1 and 6 weeks after infarction. Cardiac output and external heart work were higher, while left ventricular wall stress and collagen expression were decreased (P < 0.05) in TN-C KO mice as compared with age-matched controls at 6 weeks after infarction. TIMP-1 expression was down-regulated at 1 and 6 weeks, and TIMP-3 expression was up-regulated at 1 week (P < 0.01) after infarction in knockout mice. MMP-9 level was lower in TN-C KO at 6 weeks after infarction (P < 0.05). TIMP-3/MMP-9 ratio was higher in knockout mice at 1 and 6 weeks after infarction (P < 0.01). ACE activity in the myocardial border zone (i.e. between scar and free wall) was significantly lower in knockout than in wild-type mice 1 week after MI (P < 0.05). Conclusions Tenascin-C expression is induced by hypoxia in association with ACE activity and MMP-2 and MMP-9 elevations, thereby promoting left ventricular dilatation after MI.

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Section: Introductionmentioning

confidence: 91%

Tenascin‐C aggravates ventricular dilatation and angiotensin‐converting enzyme activity after myocardial infarction in mice

et al. 2020

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“…TNC upregulation in our ischemic MR models may have resulted from mechanical stress [25]. As an adaptation to tethering forces and flow turbulences caused by ischemic MR, TNC may at first intervene as a compensatory mechanism to protect the valve from tearing by augmenting ECM resilience as this has been observed at the myocardial level as a response to pressure overload [22]. However, its persistence becomes counterproductive, resulting in increased valvular thickness and stiffness instead of increasing the leaflet area and, therefore, jeopardizing MV coaptation.…”

Section: Discussionmentioning

confidence: 85%

Tenascin C promotes valvular remodeling in two large animal models of ischemic mitral regurgitation

et al. 2020

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Ischemic mitral regurgitation (MR) is a frequent complication of myocardial infarction (MI) characterized by adverse remodeling both at the myocardial and valvular levels. Persistent activation of valvular endothelial cells leads to leaflet fibrosis through endothelial-to-mesenchymal transition (EMT). Tenascin C (TNC), an extracellular matrix glycoprotein involved in cardiovascular remodeling and fibrosis, was also identified in inducing epithelial-to-mesenchymal transition. In this study, we hypothesized that TNC also plays a role in the valvular remodeling observed in ischemic MR by contributing to valvular excess EMT. Moderate ischemic MR was induced by creating a posterior papillary muscle infarct (7 pigs and 7 sheep). Additional animals (7 pigs and 4 sheep) served as controls. Pigs and sheep were sacrificed after 6 weeks and 6 months, respectively. TNC expression was upregulated in the pig and sheep experiments at 6 weeks and 6 months, respectively, and correlated well with leaflet thickness (R = 0.68; p < 0.001 at 6 weeks, R = 0.84; p < 0.001 at 6 months). To confirm the translational potential of our findings, we obtained mitral valves from patients with ischemic cardiomyopathy presenting MR (n = 5). Indeed, TNC was also expressed in the mitral leaflets of these. Furthermore, TNC induced EMT in isolated porcine mitral valve endothelial cells (MVEC). Interestingly, Toll-like receptor 4 (TLR4) inhibition prevented TNC-mediated EMT in MVEC. We identified here for the first time a new contributor to valvular remodeling in ischemic MR, namely TNC, which induced EMT through TLR4. Our findings might set the path for novel therapeutic targets for preventing or limiting ischemic MR.

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“…MMPs and their inhibitors, TIMPs, have been reported to be vital regulators in ECM remodelling (22). A previous study reported that a substantial increase in MMP9 and MMP2 expression levels was positively correlated with the degree of left ventricular fibrosis in a mouse model of pressure overload (23). Additionally, a previous study demonstrated that MMP9 and MMP2 expression levels were significantly increased in myocardial I/R model mice compared with sham mice (24).…”

Section: Discussionmentioning

confidence: 99%

Co‑expression of tissue kallikrein 1 and tissue inhibitor of matrix metalloproteinase 1 improves myocardial ischemia‑reperfusion injury by promoting angiogenesis and inhibiting oxidative stress

Huang

Chen²,

et al. 2020

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Tenascin-C promotes chronic pressure overload-induced cardiac dysfunction, hypertrophy and myocardial fibrosis

Abstract: Our results are pointed toward a novel signaling mechanism that contributes to LV remodeling via MMPs upregulation, cardiomyocyte hypertrophy as well as myocardial fibrosis by TN-C under chronic pressure overload.

Cited by 42 publications

References 45 publications

Tenascin‐C aggravates ventricular dilatation and angiotensin‐converting enzyme activity after myocardial infarction in mice

Tenascin‐C aggravates ventricular dilatation and angiotensin‐converting enzyme activity after myocardial infarction in mice

Tenascin C promotes valvular remodeling in two large animal models of ischemic mitral regurgitation

Co‑expression of tissue kallikrein 1 and tissue inhibitor of matrix metalloproteinase 1 improves myocardial ischemia‑reperfusion injury by promoting angiogenesis and inhibiting oxidative stress

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