UBC Theses and Dissertations
Newly uncovered novel properties of heparanase in the heart and pancreas Zhang, Dahai
Heparanase, a protein with enzymatic and non-enzymatic properties, contributes towards disease progression and prevention. We have reported that high glucose (HG) stimulates heparanase secretion from endothelial cells (EC) to cleave cardiomyocyte heparan sulfate and release bound lipoprotein lipase (LPL) for transfer to the vascular lumen. We examined whether heparanase also has a function to release cardiomyocyte vascular endothelial growth factor (VEGF), and whether this growth factor influences cardiomyocyte fatty acid (FA) delivery. HG promoted both latent and active heparanase secretion into EC conditioned medium, an effective stimulus for releasing cardiomyocyte VEGF. Intriguingly, latent heparanase was more efficient than active heparanase in releasing VEGF from a cell surface pool. VEGF augmented cardiomyocyte intracellular calcium, AMPK phosphorylation and heparin-releasable LPL. Our data suggest that the heparanase-LPL-VEGF axis amplifies FA delivery, an adaptive mechanism that is geared to overcome the loss of glucose consumption by the diabetic heart. If prolonged, the resultant lipotoxicity could lead to cardiovascular disease in humans. Therefore, we globally overexpressed heparanase and evaluated whether excessive heparanase would exacerbate the development of diabetic cardiomyopathy. The transgenic mice (hep-tg) showed normal life span and fertility, with improved glucose homeostasis. Heparanase overexpression was associated with enhanced GSIS and hyperglucagonemia, in addition to changes in islet composition and structure. Strikingly, the pancreatic islet transcriptome was greatly altered in hep-tg mice with over 2000 genes differentially expressed. The upregulated genes were enriched for diverse functions including cell death regulation, extracellular matrix component synthesis, and pancreatic hormone production. The downregulated genes were tightly linked to regulation of the cell cycle. In response to multiple low-dose STZ, hep-tg animals developed less severe hyperglycemia compared to WT, an effect likely related to their remaining beta cells that were more functionally efficient. In animals given a single high dose of STZ, causing severe hyperglycemia related to the catastrophic loss of insulin, hep-tg mice continued to have significantly lower blood glucose. In these mice, protective pathways were uncovered for managing hyperglycemia and include augmentation of FGF21 and GLP-1. Overall, this thesis uncovers opportunities to utilize both enzymatic and non-enzymatic properties of heparanase in managing diabetes and its complications.
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