Molecular Research of the Etiology and Treatment of Hypertension

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)进行了遗传筛查。到目前为止，我们已经检测到了两个与血压相关的基因：一个是第4染色体上的NPY基因，它引起血压升高；另一个是第8染色体上的PLCdelta1基因，它与降压有关。我们还发现，10号染色体上的血管紧张素转换酶基因与卒中易感自发性高血压大鼠的盐敏感性有关，肾上腺P450；11β基因突变可能与Dahl‘s耐盐大鼠的耐盐性有关。这些结果表明，多个基因的嵌合体有助于血压水平的降低。另一方面，在使用日本人群进行的人类研究中，我们证实了血管紧张素原基因T235突变的意义，该突变已由Jeunemaitre等人在欧洲高加索人中报道。尽管我们没有通过…为了进一步证明血管紧张素转换酶基因的插入/缺失多态性与日本人血压的相关性，我们证明了血管紧张素转换酶基因的缺失多态性不仅是日本人心肌梗死的危险因素，也是日本人经皮腔内血管成形术后再狭窄的潜在危险因素。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。反义寡聚体与HVJ脂质体复合后，大鼠血压下降。这些结果表明，HVJ-脂质体有可能成为研究肾素-血管紧张素系统的一种很好的工具，并有望成为高血压的一种新的基因治疗方法。较少

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