Endothelial Function and Arteriosclerosis in Klotho Mouse

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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.