■心脏在很大程度上依赖于外部脂肪酸(FA)来产生能量。已显示VEGFB(血管内皮生长因子B)通过上调FA转运蛋白来促进内皮FA摄取。然而,它对LPL(脂蛋白脂肪酶)介导的脂蛋白脂解的影响,用于心脏用途的FA的主要来源,是未知的。
■通过使用α-肌球蛋白重链启动子驱动心肌细胞特异性过表达来产生VEGFB转基因(Tg)大鼠。为了测量冠状动脉LPL活性,用肝素灌注Langendorff心脏。使用[18F]-甘油三酸酯-氟-6-thia-十七烷酸和[11C]-棕榈酸酯的体内正电子发射断层扫描成像来确定心脏FA的摄取。通过高分辨率呼吸测量法评估线粒体FA氧化。链脲佐菌素用于诱发糖尿病,使用超声心动图监测心功能。
■在Tg心脏中,LPL向血管腔的矢量转移受阻,导致LPL在心肌细胞内积聚,可能是由于冠状血管发育及其相关的胰岛素作用增强所致。空腹后胰岛素不足,VEGFB无阻地促进LPL运动并增加其在冠状动脉腔的活性。禁食后的体内PET成像证实,与无血浆的FA相比,VEGFB从循环脂蛋白中诱导了更多的FA对心脏的摄取。因为这与线粒体氧化增强有关,防止了心脏中的脂质积累。我们进一步检查了VEGFB对心脏代谢的这种特性是否在糖尿病及其相关的心脏功能障碍后有用。伴随着代谢灵活性的丧失。在Tg心中,糖尿病抑制心肌细胞VEGFB基因表达和蛋白质分泌及其下游受体信号,可以解释其缺乏心脏保护的影响。
■我们的研究强调了VEGFB在LPL衍生的FA供应和利用中的新作用。在糖尿病中,VEGFB作用的丧失可能导致代谢不灵活,脂毒性,和糖尿病心肌病的发展。
The heart relies heavily on external fatty acid (FA) for energy production. VEGFB (vascular endothelial growth factor B) has been shown to promote endothelial FA uptake by upregulating FA transporters. However, its impact on LPL (lipoprotein lipase)-mediated lipolysis of lipoproteins, a major source of FA for cardiac use, is unknown.
VEGFB transgenic (Tg) rats were generated by using the α-myosin heavy chain promoter to drive cardiomyocyte-specific overexpression. To measure coronary LPL activity, Langendorff hearts were perfused with heparin. In vivo positron emission tomography imaging with [18F]-triglyceride-fluoro-6-thia-heptadecanoic acid and [11C]-palmitate was used to determine cardiac FA uptake. Mitochondrial FA oxidation was evaluated by high-resolution respirometry. Streptozotocin was used to induce diabetes, and cardiac function was monitored using echocardiography.
In Tg hearts, the vectorial transfer of LPL to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes, an effect likely due to coronary vascular development with its associated augmentation of insulin action. With insulin insufficiency following fasting, VEGFB acted unimpeded to facilitate LPL movement and increase its activity at the coronary lumen. In vivo PET imaging following fasting confirmed that VEGFB induced a greater FA uptake to the heart from circulating lipoproteins as compared with plasma-free FAs. As this was associated with augmented mitochondrial oxidation, lipid accumulation in the heart was prevented. We further examined whether this property of VEGFB on cardiac metabolism could be useful following diabetes and its associated cardiac dysfunction, with attendant loss of metabolic flexibility. In Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling, effects that could explain its lack of cardioprotection.
Our study highlights the novel role of VEGFB in LPL-derived FA supply and utilization. In diabetes, loss of VEGFB action may contribute toward metabolic inflexibility, lipotoxicity, and development of diabetic cardiomyopathy.