A Novel Mechanism for Vascular Insulin Resistance in Normotensive Young SHRs Hypoadiponectinemia and Resultant APPL1 Downregulation
A Novel Mechanism for Vascular Insulin Resistance in Normotensive Young SHRs Hypoadiponectinemia and Resultant APPL1 Downregulation
复制标题
血压正常的年轻 SHR 中血管胰岛素抵抗的新机制低脂联素血症和由此导致的 APPL1 下调
DOI：
10.1161/hypertensionaha.111.00728
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发表时间：
2013-05-01
期刊：
影响因子：
8.3
通讯作者：
Gao, Feng
中科院分区：
文献类型：
--
作者：
Xing, Wenjuan;Yan, Wenjun;Gao, Feng
血管胰岛素抵抗导致外周血管阻力升高和随后的高血压。临床观察表明，血浆脂联素浓度降低与高血压显著相关。本研究旨在探讨低脂联素血症是否在系统性高血压发生前诱导血管胰岛素抵抗及其机制。采用4周龄自发性高血压大鼠（ySHR，血压正常）和脂联素基因敲除（KO; APN（-/-））小鼠，研究低脂联素血症在胰岛素诱导的阻力血管舒张中的作用。与年龄匹配的Wistar-Kyoto对照组相比，ySHR表现出明显的血管胰岛素抵抗，这一点通过肠系膜小动脉对胰岛素的血管舒张反应减弱得到证明。ySHR的血清脂联素和肠系膜小动脉APPL 1（介导脂联素信号传导的衔接蛋白）表达显著降低。此外，Akt和内皮NO合成酶磷酸化和NO的生产在小动脉显着减少，而细胞外信号调节蛋白激酶1/2（ERK 1/2）磷酸化和内皮素-1分泌增加ySHR。APN（-/-）小鼠的APPL 1表达和胰岛素引起的血管舒张功能显著降低。更重要的是，在体内用脂联素的球状结构域治疗ySHR 1周增加APPL 1表达和胰岛素诱导的血管舒张，并恢复胰岛素刺激的内皮血管舒张剂NO和血管收缩剂内皮素-1之间的平衡。在培养的人脐静脉内皮细胞中，脂联素球状结构域上调APPL 1的表达。抑制APPL 1表达的小干扰RNA显着钝化脂联素诱导的胰岛素增敏的球状域，证明了减少Akt/内皮NO合酶和增强ERK 1/2磷酸化。总之，低脂联素血症诱导APPL 1在阻力血管中下调，通过差异调节血压正常的ySHR血管内皮中的Akt/内皮NO合酶/NO和ERK 1/2/内皮素-1通路，促进血管胰岛素抵抗的发展。（高血压。2013; 61：1028-1035）。.在线补充资料
Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. Clinical observation showed that lower plasma adiponectin concentration is significantly associated with hypertension. This study was aimed to determine whether hypoadiponectinemia induces vascular insulin resistance before systemic hypertension and the underlying mechanisms. Four-week-old young spontaneously hypertensive rats (ySHRs, normotensive) and adiponectin knockout (KO; APN(-/-)) mice were used to evaluate the role of hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. ySHRs showed significant vascular insulin resistance as evidenced by the blunted vasorelaxation response to insulin in mesenteric arterioles compared with that of age-matched Wistar-Kyoto controls. Serum adiponectin and mesenteric arteriolar APPL1 (an adaptor protein that mediates adiponectin signaling) expression of ySHRs were significantly reduced. In addition, Akt and endothelial NO synthase phosphorylation and NO production in arterioles were markedly reduced, whereas extracellular signal-regulated protein kinases 1/2 (ERK1/2) phosphorylation and endothelin-1 secretion were augmented in ySHRs. APN(-/-) mice showed significantly decreased APPL1 expression and vasodilation evoked by insulin. More importantly, treatment of ySHRs in vivo with the globular domain of adiponectin for 1 week increased APPL1 expression and insulin-induced vasodilation, and restored the balance between insulin-stimulated endothelial vasodilator NO and vasoconstrictor endothelin-1. In cultured human umbilical vein endothelial cells, globular domain of adiponectin upregulated APPL1 expression. Suppression of APPL1 expression with small interfering RNA markedly blunted the globular domain of adiponectin-induced insulin sensitization as evidenced by reduced Akt/endothelial NO synthase and potentiated ERK1/2 phosphorylations. In conclusion, hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by differentially modulating the Akt/endothelial NO synthase/NO and ERK1/2/endothelin-1 pathways in vascular endothelium in normotensive ySHRs. (Hypertension. 2013; 61: 1028-1035.) . Online Data Supplement