Xiao Zhang

Heparanase is elevated in various pathological conditions, primarily cancer and inflammation. To investigate the significance and involvement of heparanase in liver fibrosis, we compared the susceptibility of wild-type (WT) and heparanase-overexpressing transgenic (Hpa-tg) mice to carbon tetrachloride (CCL4)-induced fibrosis. In comparison with WT mice, Hpa-tg mice displayed a severe degree of tissue damage and fibrosis, including higher necrotic tendency and intensified expression of smooth muscle actin. While damage to the WT liver started to recover after the acute phase, damage to the Hpa-tg liver was persistent. Recovery was attributed, in part, to heparanase-stimulated autophagic activity in response to CCL4, leading to increased apoptosis and necrosis. The total number of stellate cells was significantly higher in the Hpa-tg than the WT liver, likely contributing to the increased amounts of lipid droplets and smooth muscle actin. Our results support the notion that heparanase enhances inflammatory responses, and hence may serve as a target for the treatment of liver damage and fibrosis.

Heparin is a polysaccharide expressed in animal connective tissue-type mast cells. Owing to the special pentasaccharide sequence, heparin specifically binds to antithrombin (AT) and increases the inhibitory activity of AT towards coagulation enzymes. Heparin isolated from porcine intestinal mucosa has an average molecular weight of 15 kDa, while heparins recovered from rat skin and the peritoneal cavity were 60–100 kDa and can be fragmented by the endo-glucuronidase heparanase in vitro. In this study, we have examined heparin isolated from in vitro matured fetal skin mast cells (FSMC) and peritoneal cavity mast cells (PCMC) collected from wildtype (WT), heparanase knockout (Hpa-KO), and heparanase overexpressing (Hpa-tg) mice. The metabolically ³⁵S-labeled heparin products from the mast cells of WT, Hpa-KO, and Hpa-tg mice were compared and analyzed for molecular size and AT-binding activity. The results show that PCMC produced heparins with a size similar to heparin from porcine intestinal mast cells, whilst FSMC produced much longer chains. As expected, heparanase overexpression resulted in the generation of smaller fragments in both cell types, while heparins recovered from heparanase knockout cells were slightly longer than heparin from WT cells. Unexpectedly, we found that heparanase expression affected the production of total glycosaminoglycans (GAGs) and the proportion between heparin and other GAGs but essentially had no effect on heparin catabolism.

The increased risk of Alzheimer’s disease (AD) associated with specific apolipoprotein E (ApoE) isoforms appears to relate to altered amyloid-β (Aβ) homeostasis. Clearance of Aβ from the brain is reduced in the presence of the AD-associated ApoE4 isoform, which may contribute to the accumulation of Aβ deposits in the parenchyma and vasculature. The low-density lipoprotein receptor-related protein 1 (LRP1) and heparan sulfate proteoglycans (HSPGs), both established ApoE receptors, are involved in Aβ uptake, with LRP1 additionally implicated in Aβ transcytosis across the blood–brain barrier. In this study, we detected the co-distribution of heparan sulfate (HS), ApoE and LRP1 in Aβ(1-40)-positive brain microvessels from individuals with Down’s syndrome diagnosed with AD. In addition, ApoE was pulled-down from AD cerebrospinal fluid with anti-Aβ antibodies. Using Chinese hamster ovary cells deficient in HS or LRP1, we found that ApoE increases cell association of Aβ in a HSPG- and LRP1-dependent manner; and further, ApoE processing is altered in the absence of cellular HS. These interactions may facilitate Aβ clearance from the brain, but if overwhelmed could contribute to Aβ accumulation and the pathogenesis of AD.