The Responses of Hyperglycemic Dividing Mesangial Cells to Heparin Are Mediated by the Non-reducing Terminal Trisaccharide

Abstract

Background: Heparin prevents intracellular hyaluronan synthesis and subsequent autophagy in hyperglycemic dividing mesangial cells. Results: The non-reducing terminal trisaccharide of heparin is sufficient for this response. Conclusion: This heparin trisaccharide motif is exposed by the mammalian heparanase and is recognized by a receptor on dividing cells. Significance: The trisaccharide does not have the anti-coagulant properties of heparin.

Intracellular Hyaluronan Synthesis Impairs Hematopoiesis in Diabetes that can be Prevented by Heparin

“…We have shown that heparin interferes with intracellular HA synthesis, ER stress and the induced inflammatory responses in hyperglycemic stressed cells [8,13,29]. Further, the non-reducing terminal trisaccharide of heparin, Hep-Tri, is sufficient to reverse the hyperglycemic stress responses [14]. This is very significant because Hep-Tri lacks the deleterious side effects of heparin.…”

“…Hyperglycemic: Cells that divide in hyperglycemic glucose levels activate HASs in intracellular membranes entering S phase. This inserts the large, polyanionic HA intracellularly into ER, Golgi and transport vesicles, which induces ER stress and autophagy responses and extrusion of an extracellular monocyte-adhesive HA matrix after division [8,14]. Heparin/Hep-Tri: Low concentrations (Kd ~20 nM) of heparin and of Hep-Tri prevents the intracellular HA synthesis and reprograms the cells to synthesize a monocyte-adhesive extracellular HA matrix after division [8,14].…”

“…However, the molecular and cellular mechanism(s) underlying the roles of heparin are still unclear. Low concentrations (Kd ~20 nM) of heparin prevents the intracellular HA synthesis in hyperglycemic dividing bone marrow progenitor cells and reprograms them to synthesize a monocyte-adhesive extracellular HA matrix after division (Figure 1, Heparin/Hep-Tri) [8,13,14]. We propose that the tissue repairing monocytes/ macrophages (Mtr) under hyperglycemia treated with heparin effectively remove the HA matrix without initiating the inflammatory and fibrotic responses, which allows the cells and tissue to maintain their functions while still synthesizing a monocyte-adhesive HA matrix in response to the hyperglycemia.…”

Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

“…KDM5B modulates the expression of tumor suppressors and oncogenes by regulating the methylation levels of H3K4 in cancer cells [28,31]. A study by Wang et al (2015) used high risk B-ALL cells to investigate regulation of this important global epigenetic regulator, KDM5B [32]. Increased expression of KDM5B was observed in B-ALL cells compared to normal bone marrow.…”

The journey of hyaluronan research in the Journal of Biological Chemistry

“…Subsequent studies showed that low concentrations of heparin (ϳ0.3 g/ml) were sufficient 1) to prevent the intracellular hyaluronan synthesis and autophagy and 2) to re-program the cells to finish cell division and then synthesize the extensive extracellular hyaluronan matrix that is monocyte-adhesive (47). Furthermore, the nonreducing trisaccharide of heparin (Hep-Tri) (K d ϳ20 nM) is sufficient (48). These results provide evidence that hyperglycemic dividing cells have a cell-surface receptor that interacts with the Hep-Tri to re-program the cells to block intracellular hyaluronan synthesis.…”