Maekawa Yoshihiro, Ishikawa Kazuhiko, Yasuda Osamu, Oguro Ryosuke, Hanasaki Hiroko, Kida Iwao, Takemura Yukihiro, Ohishi Mitsuru, Katsuya Tomohiro, Rakugi Hiromi
Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Endocrine. 2009 Jun;35(3):341-6. doi: 10.1007/s12020-009-9181-3. Epub 2009 Apr 15.
Klotho is a senescence suppressor protein that, when overexpressed, extends the lifespan of mice. Klotho-disrupted mice exhibit atherosclerosis and endothelial dysfunction, which led us to investigate the effect of the Klotho protein on vascular inflammation, particularly adhesion molecule expression. In this study, human umbilical vein endothelial cells (HUVECs) were preincubated with Klotho protein and then exposed to tumor necrosis factor-alpha (TNF-alpha) or vehicle. Reverse transcription-PCR and Western blot analyses revealed that Klotho suppressed TNF-alpha-induced expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). NF-kappaB activation, IkappaB phosphorylation induced by TNF-alpha were also attenuated by Klotho protein administration. The inhibition of eNOS phosphorylation by TNF-alpha was reversed by Klotho. Furthermore, Klotho inhibited TNF-alpha-induced monocyte adhesion to HUVECs and suppressed adhesion molecule expression in an organ culture of the rat aorta. These results suggest that Klotho suppresses TNF-alpha-induced expression of adhesion molecules and NF-kappaB activation. Klotho may have a role in the modulation of endothelial inflammation.
klotho是一种衰老抑制蛋白，过度表达时可延长小鼠寿命。klotho基因敲除的小鼠表现出动脉粥样硬化和内皮功能障碍，这促使我们研究klotho蛋白对血管炎症，特别是黏附分子表达的影响。在本研究中，人脐静脉内皮细胞（HUVECs）先用klotho蛋白预孵育，然后暴露于肿瘤坏死因子-α（TNF-α）或溶剂中。逆转录-聚合酶链反应（RT-PCR）和蛋白质免疫印迹分析显示，klotho抑制TNF-α诱导的细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）的表达。给予klotho蛋白也可减弱TNF-α诱导的NF-κB活化、IκB磷酸化。klotho可逆转TNF-α对内皮型一氧化氮合酶（eNOS）磷酸化的抑制作用。此外，klotho抑制TNF-α诱导的单核细胞与HUVECs的黏附，并抑制大鼠主动脉器官培养物中黏附分子的表达。这些结果表明，klotho抑制TNF-α诱导的黏附分子表达和NF-κB活化。klotho可能在内皮炎症的调节中发挥作用。
