Inflammatory Cytokines and Fatty Acids Regulate Endothelial Cell Heparanase Expression

Abstract

Heparan sulfates, the carbohydrate chains of heparan sulfate proteoglycans, play an important role in basement membrane organization and endothelial barrier function. We explored whether endothelial cells secrete a heparan sulfate degrading heparanase under inflammatory conditions and what pathways were responsible for heparanase expression. Heparanase mRNA and protein by Western blot were induced when cultured endothelial cells were treated with cytokines, oxidized low-density lipoprotein (LDL) or fatty acids. Heparanase protein in the cell media was induced 2-10-fold when cells were treated with tumor necrosis factor alpha (TNFalpha) or interleukin 1beta (IL-1beta). Vascular endothelial growth factor (VEGF), in contrast, decreased heparanase secretion. Inhibitors to nuclear factor-kappaB (NFkappaB), PI3-kinase, MAP kinase, or c-jun kinase (JNK) did not affect TNFalpha-induced heparanase secretion. Interestingly, inhibition of caspase-8 completely abolished heparanase secretion induced by TNFalpha. Fatty acids also induced heparanase, and this required an Sp1 site in the heparanase promoter. Immunohistochemical analyses of cross sections of aorta showed intense staining for heparanase in the endothelium of apoE-null mice but not wild-type mice. Thus, heparanase is an inducible inflammatory gene product that may play an important role in vascular biology.

Reactive oxygen species mediate high glucose-induced heparanase-1 production and heparan sulphate proteoglycan degradation in human and rat endothelial cells: a potential role in the pathogenesis of atherosclerosis

“…TNF-α, IL-1β and fatty acids are able to induce HPR1 production in endothelial cells in vitro [42]. Immunohistochemical analyses of cross sections of aorta revealed intense staining for HPR1 in the endothelium of Apoe-null mice but not in that of wild-type mice [42]. In our study, we found that HRP1 was highly abundant in endothelial cells in atherosclerotic plaques from nondiabetic patients.…”

“…For example, HPR1 is produced locally by the endothelium at the site of delayed-type hypersensitivity-associated inflammation, and TNF-α and IFN-γ can induce HPR1 production in cultured endothelial cells [41]. TNF-α, IL-1β and fatty acids are able to induce HPR1 production in endothelial cells in vitro [42]. Immunohistochemical analyses of cross sections of aorta revealed intense staining for HPR1 in the endothelium of Apoe-null mice but not in that of wild-type mice [42].…”

Involvement and Regulation of Heparanase in Prostate Cancer Progression

“…Furthermore, TNF␣ and IFN-␥, key mediators of DTH inflammation, 3,43,44 up-regulate heparanase gene expression and increase heparanase enzymatic activity in cultured endothelial cells. Our data on heparanase induction by TNF␣ are in agreement with the previously reported ability of TNF␣ to augment ECM degradation by endothelial cells 56 and are consistent with a recent report by Chen et al 45 In the latter study, caspase 8 was identified as a part of a molecular pathway that underlies TNF␣-induced heparanase secretion by endothelial cells. The molecular mechanism through which IFN␥ augments heparanase expression remains to be further investigated.…”

Polyanionic Microbicides Modify Toll-Like Receptor-Mediated Cervicovaginal Immune Responses

“…DxS and PSS may act as synthetic analogs of heparan sulfate and other sulfated glycosaminoglycans, which regulate the function of chemokines, e.g., IL-8 (59). The sequestration of proinflammatory cytokines at the cell surface has been shown to induce the synthesis and secretion of heparanase, an enzyme that cleaves heparan sulfate in epithelial and endothelial cells and has proinflammatory activity (13). Thus, the polyanion sequestration of cytokines may have anti-inflammatory but also proinflammatory consequences and deserves further investigation.…”