Abstract 15262: The Adhesion Site Transmembrane Proteoglycan Syndecan-4; an Integrator of Pro-Hypertrophic and Pro-Inflammatory Signaling in the Heart?
Cellular adhesion sites such as the cardiomyocyte Z-disc and fibroblast focal adhesion (FA) are emerging hot spots for cardiac disease. Particularly, transmembrane adhesion proteins are thought to be important for mechanical and inflammatory responses, critical stimuli for pathological cardiac remodeling. We have shown that mice lacking syndecan-4, a transmembrane Z-disc and FA proteoglycan, develop premature failure with impaired mechanical load-induced pro-hypertrophic signaling. Syndecan-4 is up-regulated in human and murine hypertrophic myocardium, and we here investigated mechanisms regulating its cardiac expression and syndecan-4-mediated pro-inflammatory signaling in response to pressure overload. Cardiac syndecan-4 mRNA correlated to TNFα, IL-1β, IL-6 and TGFβ after aortic banding (AB) in mice, suggesting that pro-inflammatory cytokines induce syndecan-4 in vivo. Indeed, syndecan-4 mRNA was elevated in neonatal rat cardiomyocytes and fibroblasts by TNFα (~2-fold), IL-1β (∼2-fold) and LPS (∼2/∼5-fold). ANGII, NE, CXCL16, IL-18, TGFβ and IL-6 had no effect. Interestingly, cyclic mechanical stretch induced syndecan-4 mRNA ∼1.5-fold in cardiomyocytes, but not in fibroblasts. In fibroblasts, immunohistochemistry revealed that TNFα and IL-1β stimulated formation of syndecan-4-dependent mature FAs. Bioinformatical analyses identified pro-inflammatory and pro-hypertrophic NF-κB and NFAT transcription factor sites in the syndecan-4 promoter. Accordingly, blocking NF-κB inhibited TNFα-, IL-1β- and LPS-induced syndecan-4 expression. Moreover, the calcineurin-NFAT blocker CsA inhibited TNFα-induced syndecan-4 expression, and NFAT-luciferase and the NFAT target gene RCAN1-4 confirmed that TNFα activated NFAT. Importantly, syndecan-4 overexpression in HEK293-cells previously shown to activate NFAT also activated NFκB. In syndecan-4 knock-out hearts after AB, T-cell specific CD3/CD4/CD8 mRNA was reduced, suggesting impaired inflammation. Cardiac expression of the adhesion proteoglycan syndecan-4 is induced by mechanical and inflammatory signals, affecting immune cell infiltration and hypertrophic remodeling. We suggest syndecan-4 to integrate pro-hypertrophic and pro-inflammatory signaling.
- © 2012 by American Heart Association, Inc.