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Vascular endothelial growth factor B and its action in the diabetic heart

University of British Columbia

Fatty acid (FA) provision to the heart is from cardiomyocyte and adipose depots, plus lipoprotein lipase (LPL) action. Changes in cardiac metabolism (reduced glucose, greater FA utilization) is a major contributor towards diabetic cardiomyopathy. Vascular endothelial growth factor B (VEGFB) can regulate coronary angiogenesis and influence energy metabolism. Multiple models of heart failure have indicated a significant drop in VEGFB. In this thesis we hypothesized that there is a role for VEGFB in diabetic cardiomyopathy. The objectives of this thesis were to: Determine the changes in cardiac metabolism following diabetes with its effect on VEGFB production. Investigate the mechanisms behind VEGFB action in the heart subsequent to diabetes. Identify the potential benefits of VEGFB following chronic diabetes. With increasing severity of diabetes and dramatic loss of insulin, the heart is unable to control its own FA supply using LPL and undergoes dramatic reprogramming that is linked to handling of excess FA that arise from adipose tissue. This transition results in a cardiac metabolic signature that exhibits mitochondrial FA overload, oxidative stress, triglyceride storage and cell death. Under these conditions VEGFB production is impaired. Mechanistically, the immediate response to high glucose and the secretion of endothelial heparanase is the release of cardiomyocyte surface bound VEGFB, which triggers signaling pathways and gene expression to influence cardiomyocyte (autocrine action) and endothelial cell (paracrine effects) survival. Defects in numerous VEGFB pathways were associated with an increased cell death signature in our models of diabetes. Overexpression of VEGFB in the heart can regulate coronary angiogenesis and influence energy metabolism and we tested whether these effects can overcome the detrimental consequences of diabetes. VEGFB overexpression induced an angiogenic response that resulted in greater delivery of insulin, amplifying its action in the TG (transgenic) heart. Additional mechanisms contributing towards enhancing insulin sensitivity included less delivery of lipoprotein lipase-derived FA, reduced accumulation of diacylglycerols and LysoPC and lower FA metabolism. The augmented effects on insulin action were preserved following diabetes. Our data suggest that using VEGFB as a cardio protective therapy against diabetic cardiomyopathy may be an intriguing and previously unappreciated approach.

Text

2022-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/74840

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/