0303: Deleterious effects of Tenascin-C on cardiac remodeling induced by pressure overload involve microenvironment inflammation

Abstract

Tenascin-C (TN-C) is an extracellular matrix glycoprotein slightly presented in adult tissue but transiently expressed upon tissue injury. It is a well-known regulator of multiple cellular functions during embryogenesis, wound healing and cancer. Several studies suggest a potential role of inflammation induced by the expression of Danger Associated Molecular Patterns (DAMPs) in the development of heart failure. These molecules are able to synthesize pro-inflammatory cytokines through Toll Like Receptors (TLRs). TN-C is considered as a DAMP through its property to induce the expression of pro-inflammatory cytokines via TLR4. Moreover, its expression is increased in various cardiac diseases. Here, we investigate the role of TN-C on cardiac remodeling induced by pressure overload as well as its impact on cardiac fibroblasts and bone marrow derived macrophages. C57BL/6 mice WT and KO for TN-C were sacrified 6 weeks after a transverse aortic constriction (TAC). Echocardiographic measurements showed that KO mice did not exhibit an increased size of the left ventricular cavity and had a better fractional shortening compared to WT mice after TAC. The deletion of TN-C prevented pro-inflammatory environment and attenuated fibrosis. To better understand the role of TN-C, cardiac fibroblasts were transduced by a lentivector expressing GFP or TN-C. TN-C production by fibroblasts stimulated their expression of pro-inflammatory cytokines and chemokines like TNFα or CCL2. Moreover TN-C increased phagocytic activity of bone marrow derived macrophages and nitrite release in the supernatant suggesting a pro-inflammatory macrophages polarization by TN-C. TN-C seems to have a deleterious effect on cardiac remodeling. It also induces expression of pro-inflammatory genes in cardiac fibroblasts as well as pro-inflammatory macrophages polarization. Further studies are required to better understand the exact role of this protein in heart failure.