Tenascin-C in cardiac disease: a sophisticated controller of inflammation, repair, and fibrosis

Abstract

Tenascin-C (TNC) is a large extracellular matrix glycoprotein classified as a matricellular protein that is generally up-regulated at high levels during physiological and pathological tissue remodelingand is involved in important biological signaling pathways.In the heart, TNC is transiently expressed at several important steps during embryonic development and is sparsely detected in normal adult heart, but is re-expressedin a spatiotemporally restricted manner under pathological conditions associated with inflammation, such as myocardial infarction, hypertensive cardiac fibrosis, myocarditis, dilated cardiomyopathy, and Kawasaki disease. Despite its characteristic and spatiotemporally restricted expression, TNC knockout mice develop a grossly normal phenotype. However, various disease models using TNC null mice combined with in vitroexperiments have revealed many important functions for TNC and multiple molecular cascades that control cellular responses in inflammation, tissue repair, and even myocardial regeneration. TNC has context- dependent diverse functionsand, thus, may exert both harmful and beneficial effects in damaged hearts. However, TNC appears to deteriorate adverse ventricular remodeling by proinflammatory and profibrotic effects in most cases. Its specific expression also makes TNC a feasible diagnostic biomarker and target for molecular imaging to assess inflammation in the heart. Several preclinical studies have shown the utility of TNC as a biomarker for assessing the prognosis of patients and selecting appropriate therapy,particularly for inflammatory heart diseases.

Tenascin-C in Heart Diseases—The Role of Inflammation

“…pression of TNC, which may amplify inflammatory responses by creating a po back loop [13,91] (Figure 1). TNC also induced the activation of inflammasom TRL4 in epicardial cells [92].…”

Extracellular Vesicles: An Emerging Mechanism Governing the Secretion and Biological Roles of Tenascin-C

“…TnC has a prominent role in cardiovascular tissue remodeling. Almost invariably, TnC re-expression is associated with cardiovascular pathological processes coursing with inflammation, such as myocardial infarction, hypertensive cardiac fibrosis, myocarditis or dilated cardiomyopathy (65)(66)(67). Upregulation of TnC is also a hallmark of the proatherogenic vessel remodeling, driving the progression of atherosclerotic disease (AS) (68)(69)(70); however, TnC deficiency in mouse models of genetic hypercholesterolemia exacerbate atherosclerosis and promote lesions prone to rupture, reflecting the delicate balance between the physiological roles of TnC in tissue homeostasis (71).…”

Immunomodulatory Role of Tenascin-C in Myocarditis and Inflammatory Cardiomyopathy

“…On the other hand, fibroblasts are a major source of TN-C in the pathological heart ( 40 , 52 , 53 ). The combination of the two biomarkers may more accurately reflect the pathological condition of the entire heart than a single biomarker ( 54 ).…”

“…The expression of TN-C is detectable in the heart before inflammatory cell infiltration and myocytolysis become histologically apparent, persists during active inflammation, and is no longer present prior to mature collagen deposition in the healing phase in a mouse model of experimental autoimmune myocarditis ( 5 ). A major source of TN-C in the pathological heart consists of residential interstitial cells, primarily fibroblasts; however, precardiac mesodermal cells, a special population of cardiomyocytes in embryonic hearts, and several cell lines of cardiomyocytes also have the potential to produce TN-C ( 54 ). Its expression level reflects the activity of myocardial inflammation ( 40 ).…”