Neuronatin: a new inflammation gene expressed on the aortic endothelium of diabetic mice.
Neuronatin: a new inflammation gene expressed on the aortic endothelium of diabetic mice.
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作者：
Mzhavia N;Yu S;Ikeda S;Chu TT;Goldberg I;Dansky HM
目的——鉴定肥胖和糖尿病中改变的动脉基因和通路。研究设计和方法——使用小鼠 Affymetrix 阵列获得肥胖和糖尿病 db/db、高脂肪饮食喂养的 C57BL/6J 小鼠和对照小鼠的主动脉基因表达谱。选择神经蛋白（Nnat）进行进一步分析。为了确定 Nnat 的功能，使用重组腺病毒 (Ad-Nnat) 在原代内皮细胞和体内小鼠主动脉中过表达 Nnat 基因。结果——Nnat（一种血管功能未知的基因）在 db/db 和高脂饮食喂养小鼠的主动脉中表达上调。 db/db 小鼠主动脉内皮细胞中 Nnat 基因表达增加。 Nnat 蛋白定位于主动脉内皮，并在 db/db 小鼠的内皮中选择性增加。 Ad-Nnat 感染原代人主动脉内皮细胞 (HAEC) 会增加一组核因子-κB (NF-κB) 调节基因的表达，包括炎症细胞因子、趋化因子和细胞粘附分子。 Ad-Nnat 体内感染小鼠颈动脉会增加血管细胞粘附分子 1 蛋白的表达。 HAEC 中 NF-κB 的 Nnat 激活和炎症基因表达是通过不同于肿瘤坏死因子-α 的途径介导的。 Nnat 表达刺激 p38、Jun NH2 末端激酶、细胞外信号相关激酶和 AKT 激酶磷酸化。磷脂酰肌醇 3-激酶和 p38 抑制剂可阻止 Nnat 介导的 NF-κB 诱导基因表达激活。结论——肥胖和糖尿病小鼠血管内皮细胞中 Nnat 表达增加。 Nnat 对体外和体内炎症途径的影响表明该新基因在糖尿病血管疾病中的病理生理学作用。
OBJECTIVE—Identification of arterial genes and pathways altered in obesity and diabetes. RESEARCH DESIGN AND METHODS—Aortic gene expression profiles of obese and diabetic db/db, high-fat diet–fed C57BL/6J, and control mice were obtained using mouse Affymetrix arrays. Neuronatin (Nnat) was selected for further analysis. To determine the function of Nnat, a recombinant adenovirus (Ad-Nnat) was used to overexpress the Nnat gene in primary endothelial cells and in the mouse aorta in vivo. RESULTS—Nnat, a gene of unknown vascular function, was upregulated in the aortas of db/db and high-fat diet–fed mice. Nnat gene expression was increased in db/db mouse aorta endothelial cells. Nnat protein was localized to aortic endothelium and was selectively increased in the endothelium of db/db mice. Infection of primary human aortic endothelial cells (HAECs) with Ad-Nnat increased expression of a panel of nuclear factor-κB (NF-κB)-regulated genes, including inflammatory cytokines, chemokines, and cell adhesion molecules. Infection of mouse carotid arteries in vivo with the Ad-Nnat increased expression of vascular cell adhesion molecule 1 protein. Nnat activation of NF-κB and inflammatory gene expression in HAECs was mediated through pathways distinct from tumor necrosis factor-α. Nnat expression stimulated p38, Jun NH2-terminal kinase, extracellular signal–related kinase, and AKT kinase phosphorylation. Phosphatidylinositol 3-kinase and p38 inhibitors prevented Nnat-mediated activation of NF-κB–induced gene expression. CONCLUSIONS—Nnat expression is increased in endothelial cells of obese and diabetic mouse blood vessels. The effects of Nnat on inflammatory pathways in vitro and in vivo suggest a pathophysiological role of this new gene in diabetic vascular diseases.