Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB
Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB
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DOI：
10.2337/db15-0122
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发表时间：
2016-01-01
期刊：
影响因子：
7.7
通讯作者：
Gomez, Maria F.
中科院分区：
文献类型：
--
作者：
Berglund, Lisa M.;Lyssenko, Valeriya;Gomez, Maria F.
葡萄糖依赖型促胰岛素多肽(GIP)是一种胰岛素样激素，具有超出血糖控制的胰外效应。在这里，我们展示了GIP信号在血管系统中意想不到的作用。GIP通过局部释放ET-1和激活CREB诱导小鼠动脉中促动脉粥样硬化细胞因子骨桥蛋白(OPN)的表达。输注GIP可增加健康个体的血浆OPN浓度。严重肢体缺血患者血浆内皮素-1与骨桥蛋白浓度呈正相关。与对照组相比，有心血管疾病(心肌梗塞、中风)病史的个体的空腹GIP浓度更高。在有症状(中风、短暂性脑缺血发作、股骨头坏死)的颈动脉内膜切除术患者中，GIP受体(GIPR)和OPN mRNA的表达水平高于无症状患者，并且表达与不稳定和炎症斑块的特征参数(脂质堆积增加、巨噬细胞浸润和平滑肌细胞含量减少)相关。虽然GIPR在人、小鼠、大鼠和猪的健康动脉中主要是内皮细胞表达，但在培养条件下观察到内皮细胞和平滑肌细胞显著上调，产生一种“血管疾病样”表型。此外，GIPR基因中常见的rs10423928变异与2型糖尿病患者中风风险的增加有关。
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a "vascular disease-like" phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes.