Molecular mechanisms of vascular aging : analysis of a newly developed aging mouse

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Arteriosclerosis caused by aging is recognized to be a crucial risk factor of cardiovascular disease. We recently established Klotho mouse that revelas age-related disorders including arteriosclerosis. The Klotho gene encodes a novel cell surface protein of 1014 amino acids. The extracellular domain consists of two intenal repeats, which exhibit 20-40 % sequence identity to bglucosidases of bacteria and plants as well as to mammalian lactase glycosylceramidase. In situ hybridization analysis shows Klotho mRNA expression in the distal convoluted tubules in kidney as well as cholid plexus in brain. There is an intense immunoreactivity of Klotho in the convoluted tubules of the normal kidney, while no reactivity detected in an atrophic kidney.We demonstrate that the vasodilator response of aorta to acetylcholine is significantly attenuated in and 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. ACE inhibitor and angiotensin II type I receptor antagonist partially improves endothelium-dependent relaxation of aorta in heterozygous Klotho mice. These results suggest that the Klotho protein protects the cardiovascular system through endothelium-derived NO production by humoral pathways.Transcription factors in smooth muscle cell, like BTEB2 and Hex, are involved in regulation of genes induced during vascular remodeling, such as SMemb or tissue factor genes.Immunohistochemistry at two weeks after balloon-injured rat aorta showed that both Hex and BTEB2 are induced in adventitia followed by expression in neointima. In situ hybridization using riboprobes for BTEB2 and Hex also demonstrated that these transcription factors are excellent molecular markers for phenotypically modulated adventitial and smooth muscle cell.