Heparan sulfates in the extracellular matrix are required for a variety of biological processes, including cellular response to heparin-binding growth factors. However, little is known regarding the regulation of their expression and composition under pathophysiological conditions. In the present study, we have investigated the regulation of expression of two key heparan sulfate chain–carrying core proteins, syndecan-1 and syndecan-4, in a mouse/rat infarct model of tissue injury and repair. Induction of myocardial infarction was associated with a prompt increase in expression of both syndecan genes. Although infiltrating macrophages accounted for a substantial increase in syndecan expression, increased expression was noted in the levels of syndecan-1 mRNA in endothelial cells and syndecan-4 mRNA in cardiac myocytes. This increase in expression was limited to the immediate peri-infarct region and was absent from remote areas of the left or right ventricles. The influx of blood-derived macrophages in the heart correlated with the appearance of PR-39 peptide, which has previously been shown to increase syndecan expression in vitro. Studies in the op/op mice strain (which demonstrates sharply reduced levels of circulating monocytes) showed that myocardial infarction was associated with markedly reduced levels of macrophage influx and corresponding reduction in the expression of PR-39 and both syndecan genes. Pretreatment of op/op mice with granulocyte macrophage colony–stimulating factor restored myocardial macrophage content with corresponding restoration of PR-39/syndecan expression. In summary, myocardial infarction is associated with a distinct spatial and temporal pattern of syndecan-1 and -4 gene expression, which is induced by an influx of blood-derived macrophages.