Gene analysis of hypertension and development of new therapy

1. 我们研究了人类血管紧张素原基因核心启动子元件1 （AGCE1）变异之间的关系，该基因是血管紧张素原转录的关键调控因子。结果表明，AGCE1中C-18T多态性是日本人原发性高血压的遗传危险因素。提示血管紧张素原基因启动子功能障碍可能与高血压的遗传发病有关。心血管疾病的基因治疗转录因子NFkB在可能参与缺血再灌注心肌损伤的细胞因子和粘附分子基因的协调转激活中起关键作用。然后在大鼠心脏缺血前后转染高亲和力的合成双链DNA。我们首次成功地在体内转移NFkB诱饵寡脱氧核苷酸以减少再灌注后心肌梗死的程度，为心肌梗死提供了一种新的治疗策略。我们对人类冠状动脉粥样硬化进行了组织病理学研究。在冠状动脉粥样硬化的罪魁祸首区，我们发现血管紧张素原和血管紧张素转化酶的过度表达。我们展示了组织肾素血管紧张素系统在冠状动脉粥样硬化中作用的直接证据。

1. Gene analysis of hypertensionWe examined the association between variants in the core promotor element 1 (AGCE1) of the human angiotensinogen gene, which acts as a critical regulator of angiotensinogen transcription. The results obtained was that C-18T polymorphism in AGCE1 is a genetic risk factor for essential hypertension in Japanese. These results suggest that dysfunction of promortor element of angiotensinogen gene may be related to the genetic pathogenesis of hypertension.2. Gene therapy of cardiovascular diseasesThe transcriptional factor NFkB plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes that might be involved in myocardial damage after ischemia and reperfusion. Then we transfected synthetic double-stranded DNA with high affinity for NFkB before or after the cardiac ischemia in rats. We showed that the first successful in vivo tranfer of NFkB decoy oligodeoxynucleotides to reduce the extent of myocardial infraction following reperfusion, providing a new therapeutic strategy for myocardial infarction.3.Pathogenesis of cascular remodelingWe conducted histopathological study on the atheroscleosis in human coronary arteries. In the culpit region of coronary atherosclerosis, we showed over-expression of angiotensinogen and angiotensin converting-enzyme. We showed the direct evidence of the role of the tissue-renin angiotensin system in the coronary-aterosclerosis.