Physiological function of ageing suppression gene klotho and its role in development of adult disease

由衰老引起的动脉硬化被认为是心血管疾病的重要危险因素。我们最近建立了Klotho小鼠，它会导致包括动脉硬化在内的与年龄相关的疾病。然而，关于Klotho小鼠的内皮功能或Klotho基因产物作为循环因子的病理生理作用的信息尚不清楚。我们证明，与野生型小鼠相比，纯合子Klotho小鼠的主动脉和小动脉对乙酰胆碱的血管扩张反应显著减弱。野生型Klotho小鼠和杂合子Klotho小鼠之间的共生导致杂合子Klotho小鼠内皮功能的恢复。Klotho杂合子小鼠的尿中一氧化氮代谢产物(NO2-和NO3-)显著低于野生型小鼠(241*28nmo1/天)。我们还发现，在自发性高血压大鼠、脱氧皮质酮醋酸酯(DOCA)盐性高血压大鼠和大冢Long-Evans Tokushima Fatty(OLETF)大鼠发展为高血压、肥胖、胰岛素抵抗和高甘油三酯血症时，Kisoo基因的mRNA表达显著降低。我们得出结论，Klotho蛋白通过体液途径产生内皮来源的NO来保护心血管功能障碍。

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 pathophysiological role of klotho gene product as a circulating factor is available. We demonstrate that the vasodilator response of aorta and arterioles to acetylcholine was significantly attenuated in homozygous klotho mice as compared with wild-type mice. Parabiosis between wild-type and heterozygous klotho mice resulted in restoration of endothelial function in heterozygous Klotho mice. Nitric oxide metabolites (NO2- and NO3-) in urine are significantly lower in heterozygous Klotho mice (142 *16nmol/day) than wild-type mice (241* 28nmol/day). We also showed that kiotho mRNA expression is significantly decreased in spontaneously hypertensive rats, deoxycorticosterone acetate (DOCA) salt hypertensive rats and Otsuka Long-Evans Tokushima Fatty (OLETF) rats developing hypertension, obesity, insulin resistance, and hypertriglyceridemia.We conclude that the Klotho protein protects against the cardiovascular dysfunction through endothelium-derived NO production by humoral pathways.