Endothelial Function and Arteriosclerosis in Klotho Mouse

klotho小鼠是最近开发的实验室动物模型，其表型与人类衰老相似。小鼠kiotho基因表达缺陷导致多种与年龄相关的疾病，如动脉硬化、不育症、皮肤萎缩、骨质疏松症和肺气肿。纯合子klotho小鼠出生后3-4周外观正常，此后体重几乎没有增加，变得不活跃，在8-9周龄时过早死亡。纯合子klotho小鼠显微镜检查显示动脉内侧广泛钙化和内膜增厚。这些主动脉的组织学变化与人类衰老中所见的Monkeberg动脉硬化非常相似。血管内皮在控制血管张力和血小板在血管壁上聚集方面起着至关重要的作用。没有关于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，我们证明了杂合klotho小鼠对乙酰胆碱的反应主动脉舒张明显大于野生型小鼠。杂合子krotho小鼠尿液中一氧化氮代谢物明显低于野生型小鼠。我们证明，kiotho小鼠的心血管NO合成明显受损。一氧化氮生成障碍在许多疾病中都有报道，包括高血压、缺血性心脏病、充血性心力衰竭和高胆固醇血症。我们得出结论，klotho蛋白通过内皮衍生的NO生产来保护心血管系统。补充klotho蛋白可能是维持这些受试者和老年患者正常内皮功能的一种治疗策略，可能防止动脉硬化的发生或进展，并减少心血管疾病的发病率。

The klotho mouse is arecently developed laboratory animal model showing phenotypes resembling human aging. Defect of kiotho gene expression in mice causes multiple age-related disorders seen in humans, such as arteriosclerosis, infertility, skin atrophy, osteoporosis, and pulmonary emphysema. The appearance of homozygous klotho mice is normal as early as 3-4 weeks after birth, after which, they hardly gain body weight, become inactive, and die prematurely at 8-9 weeks of age. Microscopic findings of homozygous klotho mice show extensive arterial medial calcification as well as intimal thickening. These histological changes in aorta closely resemble Monkeberg arteriosclerosis seen in human aging.Vascular endothelium has been known to play a crucial role in the control of vascular tone and platelets aggregation on vessel wall. 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 demonstrated that aortic relaxation in response to acetylcholine in heterozygous klotho mice was significantly greater that in wild-type mice. Nitric oxide metabolites in urine were significantly lower in heterozygous klotho mice than wild-type mice.We demonstrated that cardiovascular NO synthesis in kiotho mice was significantly impaired. Impairment of NO production has been reported in numerous diseases, including hypertension, ischemic heart disease, congestive heart failure, and hypercholesterolemia. We conclude that the klotho protein protects the cardiovascular system through endothelium-derived NO production. Supplementation of klotho protein maybe anoveltherapeutic strategy to maintain normal endothelial function in these subjects and aged patients, perhaps preventing the development or progression of arteriosclerosis and reducing the incidence of cardiovascular diseases.