UBC Theses and Dissertations
Endothelial cells manage fatty acid delivery to the cardiomyocytes following diabetes Chiu, Amy Pei-Ling
In the diabetic heart, there is excessive dependence on fatty acid (FA) utilization to generate ATP. Lipoprotein lipase (LPL)-mediated hydrolysis of circulating triglyceride is suggested to be the predominant source of FA for cardiac utilization during diabetes. In the heart, LPL is produced in the cardiomyocytes and is transferred by its transporter glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) to the apical side of the endothelial cell (EC), where the enzyme is functional. We tested whether EC responds to hyperglycemia by increasing GPIHBP1. Streptozotocin diabetes increased cardiac LPL activity and GPIHBP1 gene and protein expression. Exposure of EC to high glucose-induced GPIHBP1 expression and amplified LPL shuttling across these cells. This effect coincided with an elevated secretion of heparanase, which can promote secretion of vascular endothelial growth factor (VEGF) from EC and cardiomyocytes. Recombinant VEGF induced EC GPIHBP1 mRNA and protein expression through activation of Notch signaling, which encompassed delta-like ligand 4 (DLL4) augmentation and nuclear translocation of the Notch intracellular domain. In addition, high glucose-induced secretion of heparanase is taken up by the cardiomyocyte to stimulate matrix-metalloproteinase (MMP) 9 expression and conversion of latent to active transforming growth factor-β (TGFβ). In the cardiomyocyte, TGFβ activation of RhoA enhances actin cytoskeleton rearrangement to promote LPL trafficking and secretion onto cell surface heparan sulfate proteoglycans. In the EC, TGFβ signaling promotes mesodermal homeobox 2 (Meox2) translocation to the nucleus that increases the expression of GPIHBP1, which facilitates movement of LPL to the vascular lumen. Collectively, EC, as the first responders to hyperglycemia, can release heparanase to liberate myocyte VEGF, which activates EC Notch signaling to facilitate GPIHBP1-mediated translocation of LPL across EC. Heparanase also induced MMP9 mediated activation of TGFβ. Its action on the cardiomyocyte to promote movement of LPL, together with its action on the EC to facilitate LPL shuttling are mechanisms that accelerate FA utilization by the diabetic heart. Gaining more insight into the mechanisms by which cardiac LPL is regulated may assist other researchers in devising new therapeutic strategies restore metabolic equilibrium, curb lipotoxicity, and help prevent or delay heart dysfunction characteristic of diabetes.
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