Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart
Inhibition of Endothelial Notch Signaling Impairs Fatty Acid Transport and Leads to Metabolic and Vascular Remodeling of the Adult Heart
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DOI：
10.1161/circulationaha.117.029733
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发表时间：
2018-06-12
期刊：
影响因子：
37.8
通讯作者：
Fischer, Andreas
中科院分区：
文献类型：
--
作者：
Jabs, Markus;Rose, Adam J.;Fischer, Andreas
背景：营养物质在肌肉细胞中代谢之前通过内皮细胞转运。然而，很少有人知道内皮运输过程的调节。Notch信号是发育过程中代谢和血管生成的关键调节因子。在这里，我们研究了如何在成年小鼠的内皮Notch信号的遗传和药理学操纵影响内皮脂肪酸转运，心脏血管生成，和心脏function.METHODS：内皮特异性Notch抑制通过条件遗传灭活Rbp-j在成年小鼠分析脂肪酸代谢和心脏功能。用针对Notch配体Delta样4的中和抗体处理野生型小鼠。在培养的内皮细胞和转基因mice.RESULTS：野生型小鼠与Delta样4中和抗体治疗8周受损的分数缩短和射血分数在大多数小鼠中的脂肪酸运输进行了研究。通过基因消融Rbp-j特异性抑制成年小鼠内皮中的Notch信号传导导致心脏肥大和衰竭。心脏功能受损之前，脂肪酸代谢的改变和心脏血管密度的增加。内皮Notch信号传导控制内皮脂肪酶、Angptl 4、CD 36和Fabp 4的表达，这些都是脂肪酸转运穿过血管壁所需的。在内皮特异性Rbp-j突变小鼠中，脂肪酶活性和长链脂肪酸向肌细胞的跨内皮转运受损。反过来，脂质在血浆和肝脏中积累。心肌细胞的长链脂肪酸供应减少伴随着更高的葡萄糖摄取，糖酵解中间产物浓度增加和mTOR-S6 K信号传导。治疗与mTOR抑制剂雷帕霉素或取代葡萄糖作为心脏底物喂养生酮饮食延长了内皮特异性Rbp-j缺陷mice.CONCLUSIONS：这项研究确定Notch信号作为一种新的调节剂的脂肪酸转运通过内皮细胞和作为一个重要的阻遏物的血管生成在成人心脏的生存。这些数据表明，内皮细胞控制心肌细胞的代谢和功能。
BACKGROUND: Nutrients are transported through endothelial cells before being metabolized in muscle cells. However, little is known about the regulation of endothelial transport processes. Notch signaling is a critical regulator of metabolism and angiogenesis during development. Here, we studied how genetic and pharmacological manipulation of endothelial Notch signaling in adult mice affects endothelial fatty acid transport, cardiac angiogenesis, and heart function.METHODS: Endothelial-specific Notch inhibition was achieved by conditional genetic inactivation of Rbp-j in adult mice to analyze fatty acid metabolism and heart function. Wild-type mice were treated with neutralizing antibodies against the Notch ligand Delta-like 4. Fatty acid transport was studied in cultured endothelial cells and transgenic mice.RESULTS: Treatment of wild-type mice with Delta-like 4 neutralizing antibodies for 8 weeks impaired fractional shortening and ejection fraction in the majority of mice. Inhibition of Notch signaling specifically in the endothelium of adult mice by genetic ablation of Rbp-j caused heart hypertrophy and failure. Impaired heart function was preceded by alterations in fatty acid metabolism and an increase in cardiac blood vessel density. Endothelial Notch signaling controlled the expression of endothelial lipase, Angptl4, CD36, and Fabp4, which are all needed for fatty acid transport across the vessel wall. In endothelial-specific Rbp-j-mutant mice, lipase activity and transendothelial transport of long-chain fatty acids to muscle cells were impaired. In turn, lipids accumulated in the plasma and liver. The attenuated supply of cardiomyocytes with long-chain fatty acids was accompanied by higher glucose uptake, increased concentration of glycolysis intermediates, and mTOR-S6K signaling. Treatment with the mTOR inhibitor rapamycin or displacing glucose as cardiac substrate by feeding a ketogenic diet prolonged the survival of endothelial-specific Rbp-j-deficient mice.CONCLUSIONS: This study identifies Notch signaling as a novel regulator of fatty acid transport across the endothelium and as an essential repressor of angiogenesis in the adult heart. The data imply that the endothelium controls cardiomyocyte metabolism and function.