Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart.

Cardiac muscle uses multiple sources of energy including glucose and fatty acid (FA). The heart cannot synthesize FA and relies on obtaining it from other sources, with lipoprotein lipase (LPL) breakdown of lipoproteins suggested to be a key source of FA for cardiac use. Recent work has indicated that cardiac vascular endothelial growth factor B (VEGFB) overexpression expands the coronary vasculature and facilitates metabolic reprogramming that favors glucose utilization. We wanted to explore whether this influence of VEGFB on cardiac metabolism involves regulation of LPL activity with consequent effects on lipotoxicity and insulin signaling. The transcriptomes of rats with and without cardiomyocyte-specific overexpression of human VEGFB were compared by using RNA sequencing. Isolated perfused hearts or cardiomyocytes incubated with heparin were used to enable measurement of LPL activity. Untargeted metabolomic analysis was performed for quantification of cardiac lipid metabolites. Cardiac insulin sensitivity was evaluated using fast-acting insulin. Isolated heart and cardiomyocytes were used to determine transgene-encoded VEGFB isoform secretion patterns and mitochondrial oxidative capacity using high-resolution respirometry and extracellular flux analysis. In vitro, transgenic cardiomyocytes incubated overnight and thus exposed to abundantly secreted VEGFB isoforms, in the absence of any in vivo confounding regulators of cardiac metabolism, demonstrated higher basal oxygen consumption. In the whole heart, VEGFB overexpression induced an angiogenic response that was accompanied by limited cardiac LPL activity through multiple mechanisms. This was associated with a lowered accumulation of lipid intermediates, diacylglycerols and lysophosphatidylcholine, that are known to influence insulin action. In response to exogenous insulin, transgenic hearts demonstrated increased insulin sensitivity. In conclusion, the interrogation of VEGFB function on cardiac metabolism uncovered an intriguing and previously unappreciated effect to lower LPL activity and prevent lipid metabolite accumulation to improve insulin action. VEGFB could be a potential cardioprotective therapy to treat metabolic disorders, for example, diabetes. In hearts overexpressing vascular endothelial growth factor B (VEGFB), besides its known angiogenic response, multiple regulatory mechanisms lowered coronary LPL. This was accompanied by limited cardiac lipid metabolite accumulation with an augmentation of cardiac insulin action. Our data for the first time links VEGFB to coronary LPL in regulation of cardiac metabolism. VEGFB may be cardioprotective in metabolic disorders like diabetes.