11β-HSD1抑制剂逆转老年心肌肥厚作用机理研究

项目名称： 11β-HSD1抑制剂逆转老年心肌肥厚作用机理研究

项目编号： No.81501201

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 黄敏

作者单位： 南京医科大学

项目金额： 17.5万元

中文摘要： 老年心衰高发病率除与老年人高发的高血压、冠心病有关，还与年龄增长对心脏、血管影响有关。心肌老化在老年心衰中起着“基石”作用，心肌老化所致心肌肥大不仅是心肌重构的最早环节，而且也是心肌重构恶化的首要环节和起源。近来有研究推测循环糖皮质激素（GC）增多对心脏作用与心脏组织局部GC增多对心脏作用存在明显差异，只有心脏局部组织GC增多才影响心肌重构。事实上，局部组织存在升高GC水平的关键酶―11β-羟化类固醇脱氢酶1（11β-HSD1），对组织的GC作用起决定作用，我们前期研究已发现老化鼠心肌11β-HSD1表达随龄增加、心肌肥厚加重，而热卡限制后11β-HSD1表达下降、心肌肥厚逆转、心功能改善，在高脂饮食大鼠，心肌11β-HSD1升高、心肌肥厚，予11β-HSD1抑制剂治疗后心肌肥厚逆转。因此，本课题创新性利用11β-HSD1抑制剂研究心肌老化、心肌肥厚的分子机制，为逆转心肌肥厚提供新手段。

中文关键词： 心肌肥大；11β-HSD1抑制剂；老化；心力衰竭

英文摘要： Cardiac hypertrophy plays key role in the development of heart failure in elderly individuals . It has been postulated that high serum concentration of glucocorticoid has a different effect on the heart from a local increase of corticosterone in cardiac tissue while a local increase of corticosterone in cardiac tissue has a role in myocardial remodeling.11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an reductase that catalyzes the conversion of the inactive forms of glucocorticoids(GC) to their active forms in local tissues, samplifying local glucocorticoid signaling. In our previous study, we observed a significant increase in the expression of 11β-HSD1 genes in heart of aged mice and, decreased in the expression of 11β-HSD1 genes, reversed cardiac hypertrophy and improved heart function in mice with caloric restriction.we also found reversed cardiac hypertrophy and improved heart function in high-fat diet rat treated with 11β-HSD1 inhibtor. These results indicated that 11β-HSD1 plays an vital role in cardiac aging and cardiac hypertrophy.In this proposal, we synthesised the specific 11β-HSD1 inhibitor to clarify the role of 11β-HSD1 in regulating the cardiac hypertrophy and provide therapeutic target for anti-aging and associated disease.

英文关键词： cardiac hypertrophy;11β-HSD1 inhibtor;aging;heart failure