APPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice.
APPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice.
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作者：
Wang Y;Cheng KK;Lam KS;Wu D;Wang Y;Huang Y;Vanhoutte PM;Sweeney G;Li Y;Xu A
胰岛素刺激一氧化氮（NO）依赖性血管舒张和内皮素-1（ET-1）依赖性血管收缩。然而，控制胰岛素双重血管效应的细胞机制仍不清楚。本研究旨在探讨多结构域衔接蛋白APPL 1在调节胰岛素在小鼠和内皮细胞中的血管作用中的作用。APPL 1基因敲除小鼠和APPL 1转基因小鼠都被用来评估APPL 1在调节血管反应性和内皮细胞胰岛素信号传导中的生理作用。胰岛素强效诱导8周龄小鼠肠系膜动脉的NO依赖性舒张，而胰岛素的这种作用随着年龄的增长或高脂饮食诱导的肥胖症的发展而逐渐受损。APPL 1的转基因表达可预防年龄和肥胖引起的胰岛素诱导的血管舒张功能受损，并逆转肥胖引起的胰岛素诱发的ET-1依赖性血管收缩增强。相比之下，APPL 1的遗传破坏将胰岛素的作用从血管舒张转移到血管收缩。在分子水平上，胰岛素诱导的蛋白激酶B（Akt）和内皮NO合酶的激活和NO的产生在APPLE 1转基因小鼠中增强，但在APPLE 1敲除小鼠中被废除。相反，胰岛素诱导的细胞外信号相关激酶（ERK）1/2磷酸化和ET-1表达增强APPL 1基因敲除小鼠，但APPL 1转基因小鼠减少。在内皮细胞中，APPL 1通过与Akt抑制剂Tribbles 3（TRB 3）竞争增强胰岛素刺激的Akt激活，并通过改变其上游激酶Raf-1的磷酸化状态抑制ERK 1/2信号转导。APPL 1通过调节内皮细胞中Akt依赖的NO产生和ERK 1/2介导的ET-1分泌，在协调胰岛素的血管舒张和血管收缩作用中起关键作用。
Insulin stimulates both nitric oxide (NO)-dependent vasodilation and endothelin-1 (ET-1)–dependent vasoconstriction. However, the cellular mechanisms that control the dual vascular effects of insulin remain unclear. This study aimed to investigate the roles of the multidomain adaptor protein APPL1 in modulating vascular actions of insulin in mice and in endothelial cells. Both APPL1 knockout mice and APPL1 transgenic mice were generated to evaluate APPL1’s physiological roles in regulating vascular reactivity and insulin signaling in endothelial cells. Insulin potently induced NO-dependent relaxations in mesenteric arteries of 8-week-old mice, whereas this effect of insulin was progressively impaired with ageing or upon development of obesity induced by high-fat diet. Transgenic expression of APPL1 prevented age- and obesity-induced impairment in insulin-induced vasodilation and reversed obesity-induced augmentation in insulin-evoked ET-1–dependent vasoconstriction. By contrast, genetic disruption of APPL1 shifted the effects of insulin from vasodilation to vasoconstriction. At the molecular level, insulin-elicited activation of protein kinase B (Akt) and endothelial NO synthase and production of NO were enhanced in APPL1 transgenic mice but were abrogated in APPL1 knockout mice. Conversely, insulin-induced extracellular signal–related kinase (ERK)1/2 phosphorylation and ET-1 expression was augmented in APPL1 knockout mice but was diminished in APPL1 transgenic mice. In endothelial cells, APPL1 potentiated insulin-stimulated Akt activation by competing with the Akt inhibitor Tribbles 3 (TRB3) and suppressed ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1. APPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium.
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影响因子：
37.8
作者：
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通讯作者：
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8.3
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15.3
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16.2
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