Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada.
Am J Physiol Endocrinol Metab. 2021 Dec 1;321(6):E753-E765. doi: 10.1152/ajpendo.00219.2021. Epub 2021 Nov 8.
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.
心肌利用多种能源，包括葡萄糖和脂肪酸 (FA)。心脏不能合成 FA，依赖于从其他来源获得它，脂蛋白脂肪酶 (LPL) 分解脂蛋白被认为是心脏使用 FA 的主要来源。最近的工作表明，心脏血管内皮生长因子 B (VEGFB) 的过表达扩大了冠状血管系统，并促进了有利于葡萄糖利用的代谢重编程。我们想探讨 VEGFB 对心脏代谢的这种影响是否涉及 LPL 活性的调节，从而对脂毒性和胰岛素信号产生影响。通过 RNA 测序比较了有和没有心肌细胞特异性过表达人 VEGFB 的大鼠的转录组。使用肝素孵育分离的灌注心脏或心肌细胞，以测量 LPL 活性。进行非靶向代谢组学分析以定量心脏脂质代谢物。使用速效胰岛素评估心脏胰岛素敏感性。使用分离的心脏和心肌细胞来确定转基因编码的 VEGFB 同工型分泌模式和使用高分辨率呼吸测定法和细胞外通量分析测量线粒体氧化能力。在体外，转染的心肌细胞孵育过夜，因此暴露于大量分泌的 VEGFB 同工型，而没有任何体内代谢物调节因子的混杂影响，表现出更高的基础耗氧量。在整个心脏中，VEGFB 的过表达诱导了血管生成反应，同时通过多种机制导致心脏 LPL 活性有限。这与脂质中间体、二酰基甘油和溶血磷脂酰胆碱的积累降低有关，这些物质已知会影响胰岛素作用。对外源胰岛素的反应中，转基因心脏表现出胰岛素敏感性增加。总之，对 VEGFB 对心脏代谢的功能的研究揭示了一种有趣的、以前未被认识到的效应，即降低 LPL 活性和防止脂质代谢物积累，以改善胰岛素作用。VEGFB 可能是治疗代谢紊乱（例如糖尿病）的潜在心脏保护治疗方法。在过表达血管内皮生长因子 B (VEGFB) 的心脏中，除了其已知的血管生成反应外，多种调节机制降低了冠状 LPL。这伴随着心脏脂质代谢物积累的有限增加，以及心脏胰岛素作用的增强。我们的数据首次将 VEGFB 与心脏代谢中的冠状 LPL 联系起来。VEGFB 在代谢紊乱（如糖尿病）中可能具有心脏保护作用。
