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

血管衰老的分子机制：对新开发的衰老小鼠的分析

基本信息

批准号：
09044256
负责人：
NAGAI Ryozo
金额：
$ 3.58万
依托单位：
Gunma University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

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.

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，它显示出包括动脉硬化在内的与年龄相关的疾病。Klotho基因编码一种由1014个氨基酸组成的新型细胞表面蛋白。胞外区由两个内部重复序列组成，与细菌和植物的糖苷酶以及哺乳动物的乳糖基神经酰胺酶具有20%-40%的序列同源性。原位杂交结果显示，Klotho基因在肾脏远端曲管和脑内胆汁丛均有表达。Klotho在正常肾脏的曲管中有强烈的免疫反应，而在萎缩的肾脏中没有检测到反应。我们证明与野生型Klotho小鼠相比，Klotho纯合子小鼠的主动脉对乙酰胆碱的扩血管反应显著减弱。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。血管紧张素转换酶抑制剂和血管紧张素II I型受体拮抗剂部分改善Klotho杂合子小鼠的血管内皮依赖性松弛。这些结果表明，Klotho蛋白通过体液途径产生内皮源性NO来保护心血管系统。血管细胞中的转录因子，如BTEB2和Hex，参与了血管重塑过程中诱导的基因的调节，如SMemb或组织因子基因。免疫组织化学显示，大鼠主动脉球囊损伤后2周，Hex和BTEB2均在外膜诱导，随后在新生内膜中表达。使用BTEB2和Hex的核探针的原位杂交也表明，这些转录因子是表型调控的外膜和平滑肌细胞的优秀分子标记。