11β-HSD1抑制剂逆转老年心肌肥厚作用机理研究

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.

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。

高脂饮食可致心肌肥大，但其具体分子机制尚不明确，本项目通过取雄性Wistar大鼠喂食正常饲料或高脂饮食建立高脂饮食相关的心肌肥大模型，运用超声心动图和病理组织学染色观察心脏重塑和功能改变。利用棕榈酸处理或慢病毒感染的原代新生乳鼠心室心肌细胞（NRCMs）模型进一步研究确认11β-HSD1在心肌肥大中的作用。并通过基因组芯片检测进一步揭示高脂饮食致心肌肥大的潜在机制及11β-HSD1抑制剂发挥作用的机制。研究显示，棕榈酸诱导NRCMs肥大，上调心肌细胞中11β-HSD1的表达，导致细胞增大和心肌肥大特异性基因表达显着增加。相反，在BVT.2733（11β-HSD1的选择性抑制剂）处理的或11β-HSD1缺陷的NRCM中检测到心肌细胞大小显着降低。此外，糖皮质激素受体（GR）拮抗剂RU486和盐皮质激素受体（MR）拮抗剂螺内酯均显著减弱11β-HSD1诱导的心肌细胞肥大。基因组芯片显示cAMP和钙信号通路是11β-HSD1调节心肌细胞肥大潜在的下游信号通路。与体外结果相似，BVT.2733显著减弱高脂饮食喂养大鼠的心脏肥大，并改善心脏功能。从而提示，11β-HSD1作为重要的调节因子，通过GR和MR调控心脏重塑，11β-HSD1抑制剂可能是预防高脂饮食诱导心肌肥厚的一种新的治疗方法。