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UBC Theses and Dissertations

Vascular endothelial growth factor B affects cardiac substrate utilization by regulating lipoprotein lipase Shang, Rui


In Canada, more than 11 million individuals live with diabetes or pre-diabetes. Heart failure, a leading cause of death in this disease, can result from an intrinsic malfunction of the cardiac muscle (diabetic cardiomyopathy; DCM). The etiology of DCM is complex, with changes in cardiac metabolism (reduced glucose but greater fatty acid (FA) consumption), a major culprit. This leads to a mismatch between FA delivery and utilization, leading to lipid metabolite build-up and cell death. In this milieu, protection against excessive accumulation of the precursors of triglyceride, FA or their metabolites in the diabetic heart would be advantageous. Strategies to do this include improving insulin sensitivity to lower FA uptake and/or enhancing FA oxidation in cardiomyocyte mitochondria. Vascular endothelial growth factor (VEGF) B is unique in its ability to a) enhance VEGFA-induced angiogenesis, b) trigger metabolic reprogramming and c) inhibit cell death. In hearts overexpressing VEGFB, its known angiogenic response was associated with an augmentation of cardiac insulin action. Additionally, multiple regulatory mechanisms lowered coronary lipoprotein lipase (LPL) and was accompanied by reduced cardiac lipid metabolite accumulation. With overnight fasting and reduced circulating insulin, VEGFB acts unimpeded, such that cardiac LPL-derived FA uptake took precedence over non-esterified fatty acids. Nevertheless, an augmented mitochondrial oxidation prevented lipid accumulation in the heart, highlighting the potential for VEGFB to protect against lipotoxicity. Diabetes had multiple effects on VEGFB biology, including a reduction in gene expression, protein secretion and receptor signaling. Thus, loss of VEGFB action may contribute to metabolic inflexibility and lipotoxicity, key contributors towards development of the cardiovascular complications seen during diabetes. As mechanism-directed therapeutic care for DCM is presently unavailable, further interrogation of the mechanisms behind loss of VEGFB function following diabetes is anticipated to help us advance the clinical management of DCM.

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