Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation.
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.
Maekawa
Yoshihiro
Y
Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Ishikawa
Kazuhiko
K
Yasuda
Osamu
O
Oguro
Ryosuke
R
Hanasaki
Hiroko
H
Kida
Iwao
I
Takemura
Yukihiro
Y
Ohishi
Mitsuru
M
Katsuya
Tomohiro
T
Rakugi
Hiromi
H
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005966:Glucuronidase / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000235:genetics; D000090265:Klotho Proteins; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015815:Cell Adhesion Molecules; D020672:I-kappa B Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D052250:Nitric Oxide Synthase Type III; D005966:Glucuronidase; D000090265:Klotho Proteins