老化抑制遺伝子klothoと血管病態(Agingと疾患,シンポジウム,東京女子医科大学学会第64回総会)

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It has been well recognized that patients with major coronary risk factors develop atherosclerosis in a higher frequency, but there are many atherosclerotic patients without these risk factors, suggesting the presence of other unknown risk factors regulating development of atherosclerosis. It has been known that the most important risk factor for atherosclerosis is "aging" to whatever extent the major risk factors are involved in atherogenesis. We recently identified the klotho gene as a possible regulator of human aging process. Because endothelial function is impaired in aged subjects, it is plausible to hypothesize that klotho may protect against endothelial dysfunction. Therefore, we decided to examine whether the klotho-deficient mice have endothelial dysfunction. We first found that the klotho gene product itself or its metabolites protect against endothelial dysfunction as a humoral factor because endothelium-dependent arterial dilatation was impaired in the klotho-deficient heterozygous mouse, which was improved by establishing parabiosis with a wildtype mouse but not with a heterozygous mouse. Reduced expression of the klotho gene seems to be a risk factor of arterial diseases because heterozygous mouse with apparently normal histology of the arterial wall developed hypertension with high-salt drinking water and atherosclerosis with high cholesterol diet. We also have shown that in animal models of hypertension, kidney diseases, hyperlipidemia and diabetes, all of which are known as an important risk factor for atherosclerosis, klotho gene expression was reduced in kidney. It is noteworthy that endothelial dysfunction observed in a rat model of hyperlipidemia and hyperglycemia (OLETF rat) could be improved by angiotensin converting enzyme inhibitor, which is accompanied by increased klotho gene expression in kidney. Our results suggest that klotho gene expression is regulated by local or systemic stress against kidney or the vascular wall.
東京女子医科大学の論文
1999-04-25

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