Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-κB signaling through a cAMP-dependent pathway
Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-κB signaling through a cAMP-dependent pathway
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DOI：
10.1161/01.cir.102.11.1296
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发表时间：
2000-09-12
期刊：
影响因子：
37.8
通讯作者：
Matsuzawa, Y
中科院分区：
文献类型：
--
作者：
Ouchi, N;Kihara, S;Matsuzawa, Y
背景-在许多脂肪细胞源性内分泌因子中，我们发现一种脂肪细胞源性血浆蛋白脂联素在肥胖时减少。我们最近证实，脂联素抑制肿瘤坏死因子-α（TNF-α）诱导的内皮粘附分子表达，并且冠心病患者血浆脂联素水平降低（Circulation. 1999;100：2473-2476）。然而，脂联素抑制粘附分子表达的细胞内信号尚未阐明。本研究探讨了调节内皮功能的机制adiponectin.Methods和Results-the adiponectin和人主动脉内皮细胞（HAECs）之间的相互作用进行了估计细胞ELISA使用生物素化的adiponectin。将HAEC与50 μ g/mL脂联素预孵育18小时，然后暴露于TNF-α（10 U/mL）或载体指定的时间。通过电泳迁移率变动分析测定NF-κ B-DNA结合活性。通过免疫印迹检测TNF-α诱导的磷酸化信号。脂联素以饱和方式特异性结合HAECs，并抑制TNF-α诱导的单核细胞粘附分子mRNA表达，而不影响TNF-α及其受体之间的相互作用。脂联素抑制TNF-α诱导的I κ B-α磷酸化和随后的NF-κ B活化，而不影响其他TNF-α介导的磷酸化信号，包括Jun N-末端激酶、p38激酶和Akt激酶。这种抑制作用的脂联素是伴随着cAMP的积累，并被黑色的腺苷酸环化酶抑制剂或蛋白激酶A（PKA）inhibitors. Conclusions-这些观察结果提高的可能性，脂联素，这是自然存在于血流中，调节炎症反应的内皮细胞通过cAMP-PKA和NF-κ B信号通路之间的串扰。
Background-Among the many adipocyte-derived endocrine factors, we found an adipocyte-derived plasma protein, adiponectin, that was decreased in obesity. We recently demonstrated that adiponectin inhibited tumor necrosis factor-alpha (TNF-alpha)-induced expression of endothelial adhesion molecules and that plasma adiponectin level was reduced in patients with coronary artery disease (Circulation. 1999;100:2473-2476). However, the intracellular signal by which adiponectin suppressed adhesion molecule expression was not elucidated. The present study investigated the mechanism of modulation for endothelial function by adiponectin.Methods and Results-The interaction between adiponectin and human aortic endothelial cells (HAECs) was estimated by cell ELISA using biotinylated adiponectin. HAECs were preincubated for 18 hours with 50 mu g/mL of adiponectin, then exposed to TNF-alpha (10 U/mL) or vehicle for the times indicated. NF-kappa B-DNA binding activity was determined by electrophoretic mobility shift assays. TNF-alpha-inducible phosphorylation signals were detected by immunoblotting. Adiponectin specifically bound to HAECs in a saturable manner and inhibited TNF-alpha-induced mRNA expression of monocyte adhesion molecules without affecting the interaction between TNF-alpha and its receptors. Adiponectin suppressed TNF-alpha-induced I kappa B-alpha phosphorylation and subsequent NF-kappa B activation without affecting other TNF-alpha-mediated phosphorylation signals, including Jun N-terminal kinase, p38 kinase, and Akt kinase. This inhibitory effect of adiponectin is accompanied by cAMP accumulation and is blacked by either adenylate cyclase inhibitor or protein kinase A (PKA) inhibitor.Conclusions-These observations raise the possibility that adiponectin, which is naturally present in the blood stream, modulates the inflammatory response of endothelial cells through cross talk between cAMP-PKA and NF-kappa B signaling pathways.