Sustained pressure overload induces heart failure, the main cause of mortality in the Western world. Increased understanding of the underlying molecular mechanisms is essential to improve heart failure treatment. Despite important functions in other tissues, cardiac proteoglycans have received little attention. Syndecanâ4, a transmembrane heparan sulfate proteoglycan, is essential for pathological remodeling, and we here investigated its expression and shedding during heart failure. Pressure overload induced by aortic banding for 24 h and 1 week in mice increased syndecanâ4 mRNA, which correlated with mRNA of inflammatory cytokines. In cardiac myocytes and fibroblasts, tumor necrosis factorâÎą, interleukinâ1β and lipopolysaccharide through the tollâlike receptorâ4, induced syndecanâ4 mRNA. Bioinformatical and mutational analyses in HEK293 cells identified a functional site for the proinflammatory nuclear factorâÎşB transcription factor in the syndecanâ4 promoter, and nuclear factorâÎşB regulated syndecanâ4 mRNA in cardiac cells. Interestingly, tumor necrosis factorâÎą, interleukinâ1β and lipopolysaccharide induced nuclear factorâÎşBâdependent shedding of the syndecanâ4 ectodomain from cardiac cells. Overexpression of syndecanâ4 with mutated enzymeâinteracting domains suggested enzymeâdependent heparan sulfate chains to regulate shedding. In cardiac fibroblasts, lipopolysaccharide reduced focal adhesion assembly, shown by immunohistochemistry, suggesting that inflammationâinduced shedding affects function. After aortic banding, a timeâdependent cardiac recruitment of T lymphocytes was observed by measuring CD3, CD4 and CD8 mRNA, which was reduced in syndecanâ4 knockout hearts. Finally, syndecanâ4 mRNA and shedding were upregulated in failing human hearts. Conclusively, our data suggest that syndecanâ4 plays an important role in the immune response of the heart to increased pressure, influencing cardiac remodeling and failure progression.