热卡限制类似方法——11β-HSD1抑制剂防治心肌纤维化机制研究

Senile heart failure cause serious damage to the life quality and expectancy of the elderly. Cardiac fibrosis induced by cardiac aging plays a key role in the development of senile heart failure. As we all know, calorie restriction is the most effective anti-aging means, but the mechanism is unclear. Moreover, it is difficult in clinical application due to its hunger and difficulty. The level of glucocorticoid induced by chronic stress plays an important role in aging. In our previous study, the expression of 11β-HSD1 genes of myocardial tissue in mice increased with aging.In response to CR, the expression of 11β-HSD1 genes decreased, cardiac fibrosis reversed ,heart function improved and promoter has glucocorticoid receptor binding sites of microRNAs change. We also found reversed cardiac fibrosis and improved heart function in high-fat diet rat treated with cardiac inhibtor.Therefore, we speculated that 11β-HSD1 was caloric restriction target. In this proposal, we systematically studied the molecular mechanisms of caloric restriction based on previous studies by reducing the activity of 11β-HSD1, regulating microRNAs expression and improving cardiac fibrosis. Accordingly, we synthesised the 11β-HSD1 inhibitor to develop caloric restriction mimetics in order to provide therapeutic targetof delaying cardiac aging.

老年心力衰竭严重危害老年人生活质量和寿命，心肌老化引起的心肌纤维化在老年心衰中起着基石作用。众所周知，热卡限制是最经典有效的抗衰老手段，但机制不清，由于其艰巨性也难以临床应用。因慢性应激引起的应激激素糖皮质激素水平增加在促进老化中起重要作用，我们对调节局部组织糖皮质激素水平的11β-HSD1酶研究发现：随年龄增加小鼠心肌11β-HSD1表达不断升高，而热卡限制则使其表达下降、心肌老化减轻、心肌纤维化减少、启动子具有糖皮质激素受体结合位点的miRNAs明显变化, 对高脂诱导11β-HSD1表达升高的大鼠研究发现11β-HSD1抑制剂减轻心肌老化、改善纤维化。我们推测11β-HSD1是热卡限制的作用靶点，本课题开创性研究热卡限制分子机制：通过降低11β-HSD1活性，调节miRNAs表达而改善心肌纤维化，并通过11β-HSD1抑制剂干预研究，开发热卡限制类似方法以便临床应用。

老年心力衰竭严重危害老年人生活质量和寿命，心肌老化引起的心肌纤维化在老年心衰中起着基石作用。众所周知，热卡限制是最经典有效的抗衰老手段，但机制不清，由于其艰巨性也难以临床应用。因慢性应激引起的应激激素糖皮质激素水平增加在促进老化中起重要作用，我们对调节局部组织糖皮质激素水平的关键酶——11β-羟化类固醇脱氢酶1（11β-HSD1）研究发现：随年龄增加，小鼠心肌11β-HSD1表达不断升高，而热卡限制则使其表达下降、心肌老化减轻、心肌纤维化减少。高脂饮食是老化加速器，我们进一步通过体内外研究发现：高脂饮食可诱导大鼠心肌肥厚、心脏炎症增加及心肌纤维化，进而导致心功能下降。而11β-HSD1抑制剂BVT.2733干预减轻高脂饮食引起的心肌老化、改善心肌细胞肥厚、炎症和纤维化，改善了高脂饮食大鼠心功能。同时通过全基因组芯片以及IPA通路分析发现cAMP和钙信号通路是11β-HSD1导致心肌细胞肥大的潜在信号通路。结果表明11β-HSD1可能是热卡限制的作用靶点，本课题开创性研究热卡限制分子机制，开发热卡限制类似方法以便临床应用。