Saito Y, Yamagishi T, Nakamura T, Ohyama Y, Aizawa H, Suga T, Matsumura Y, Masuda H, Kurabayashi M, Kuro-o M, Nabeshima Y, Nagai R
Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-22 Showa, Maebashi, Gunma, 371-8511, Japan.
Biochem Biophys Res Commun. 1998 Jul 20;248(2):324-9. doi: 10.1006/bbrc.1998.8943.
Arteriosclerosis caused by aging is recognized to be a crucial risk factor of cardiovascular disease. We recently established klotho mouse which causes age-related disorders including arteriosclerosis. However, no information on endothelial function of klotho mouse or the physiological role of klotho protein as a circulating factor is available. In this report, we demonstrate that 50% effective dose of aortic relaxation in response to acetylcholine in heterozygous klotho mice is significantly greater (4 x 10(-5) M) than in wild-type mice (8 x 10(-6) M, n = 7, p < 0.05) and that the vasodilator response of arterioles to acetylcholine is significantly attenuated in heterozygous (20% effective dose; 2 x 10(-6) M) and homozygous klotho mice (>1 x 10(-5) M) as compared with wild-type mice (1 x 10(-7) M, n = 7, p < 0.05). Nitric oxide metabolites (NO-2 and NO-3) in urine are significantly lower in heterozygous klotho mice (142 +/- 16 nmol/day) than wild-type mice (241 +/- 28 nmol/day, n = 13, p < 0.05). Parabiosis between wild-type and heterozygous klotho mice results in restoration of endothelial function in heterozygous klotho mice. We conclude that the klotho protein protects the cardiovascular system through endothelium-derived NO production by humoral pathways.
衰老引起的动脉硬化被认为是心血管疾病的一个关键风险因素。我们最近培育出了klotho小鼠，它会引发包括动脉硬化在内的与年龄相关的病症。然而，目前尚无关于klotho小鼠内皮功能或klotho蛋白作为循环因子的生理作用的信息。在本报告中，我们证明，杂合klotho小鼠对乙酰胆碱产生主动脉舒张反应的半数有效剂量（4×10⁻⁵M）显著高于野生型小鼠（8×10⁻⁶M，n = 7，p < 0.05），并且与野生型小鼠（1×10⁻⁷M，n = 7，p < 0.05）相比，杂合（半数有效剂量为2×10⁻⁶M）和纯合klotho小鼠中小动脉对乙酰胆碱的血管舒张反应显著减弱。杂合klotho小鼠尿液中的一氧化氮代谢产物（NO₂和NO₃）（142±16 nmol/天）显著低于野生型小鼠（241±28 nmol/天，n = 13，p < 0.05）。野生型和杂合klotho小鼠之间的联体生活导致杂合klotho小鼠的内皮功能得以恢复。我们得出结论，klotho蛋白通过体液途径由内皮细胞产生一氧化氮来保护心血管系统。
