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Molecular Research of the Etiology and Treatment of Hypertension

高血压病因及治疗的分子研究

基本信息

批准号：
04404044
负责人：
OGIHARA Toshio
金额：
$ 13.12万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

To investigate the molecular etiology of hypertension, we have conducted genetic screening of the spontaneously hypertensive rat (SHR). We have detected so far two loci which are related with blood pressure determination : one is the NPY gene on chromosome 4 which induces blood pressure elevation, and the other is the PLCdelta _1 gene on chromosome 8 with hypotensive effect. We also showed that the angiotensin converting enzyme gene on chromosome 10 is related with salt-sensitivity of stroke-prone SHR,and that the mutation of adrenal P450_<11beta> gene may be responsible for the salt-resistance of Dahl's saltresistant rats. These results suggest that the mosaic of multiple genes contributes to the degermination of the blood pressure level.On the other hand, in the human study using Japanese population, we confirmed significance of hypertensinogenic T235 variant of the angiotensinogen gene, which has been formerly reported in European Caucasians by Jeunemaitre et al. Although we failed … More to prove that the insertion/deletion polymorphism of angiotensin-converting enzyme associates with blood pressure in Japanese, we demonstrated that the deletion polymorphism of angiotensin converting enzyme gene could be a potent risk factor for not only myocardial infarction but also restenosis after percutaneous transluminal angioplasty in Japanese subjects.Using an efficient and nontoxic in vivo gene transfer method (HVJ-liposome), we produced a hypertensive model rat that is dependent on human renin. The elevated blood pressure was normalized by the intravenous administration of specific human renin inhibitor. Next, HVJ-liposomes containing oligonucleotide complementary to rat angiotensinogen gene were injected into liver. The blood pressure of the rat treated with HVJ-liposome complexed with antisense oligomer decreased. These results showed that the HVJ-liposome could be potentially a good tool for the study of the renin-angiotensin system and a furture gene therapy for hypertension. Less

为了研究高血压的分子病因学，我们对自发性高血压大鼠（SHR）进行了基因筛查。目前我们已检测到两个与血压测定相关的位点：一是4号染色体上的NPY基因，其诱导血压升高；二是8号染色体上的PLCdelta_1基因，具有降血压作用。我们还发现10号染色体上的血管紧张素转换酶基因与脑卒中易感SHR的盐敏感性有关，肾上腺P450_<11β>基因的突变可能是达尔氏耐盐大鼠的耐盐性的原因。这些结果表明，多个基因的嵌合有助于血压水平的去萌芽。另一方面，在使用日本人群的人体研究中，我们证实了血管紧张素原基因的致高血压T235变体的重要性，该变体先前已由Jeunemaitre等人在欧洲白种人中报道过。尽管我们未能证明血管紧张素转换酶基因的插入/缺失多态性与日本人的血压相关，但我们证明血管紧张素转换酶基因的缺失多态性不仅可能是日本受试者心肌梗死而且可能是经皮腔内血管成形术后再狭窄的潜在危险因素。通过无毒体内基因转移方法（HVJ-脂质体），我们制备了依赖于人肾素的高血压模型大鼠。通过静脉注射特定的人肾素抑制剂使升高的血压恢复正常。接下来，将含有与大鼠血管紧张素原基因互补的寡核苷酸的HVJ-脂质体注射到肝脏中。用与反义寡聚物复合的HVJ-脂质体处理的大鼠的血压下降。这些结果表明，HVJ-脂质体可能成为研究肾素-血管紧张素系统和未来高血压基因治疗的良好工具。较少的