补阳还五汤调控鞘脂从头合成代谢轴治疗老年性心梗后心脏重构的作用及分子机制研究

鞘脂代谢失衡参与衰老和心梗后心衰的发生发展，Des1介导的鞘脂从头合成轴与鞘脂代谢失衡密切相关，但在老年性心梗后心室重构中的作用及机制目前尚不明确。气虚血瘀是老年性心梗后心室重构的主要病机之一，我们前期证实益气活血代表方补阳还五汤具有抗心梗后心室重构的作用。本项目在前期研究基础上提出以下假说“鞘脂代谢失常是老年性心梗后心室重构向心衰发展的可能机制，Des1介导的鞘脂从头合成代谢轴是改善老年性心梗后心室重构预后的潜在靶点；补阳还五汤通过调控Des1平衡鞘脂代谢水平改善老年性心梗后心室重构”。本项目拟采用结合快速老化（Samp8）小鼠和小鼠冠脉结扎术构建老年性心梗模型，运用鞘脂代谢组学、转录组学等技术，对Des1介导的鞘脂从头合成代谢轴在心梗后心衰发展中的作用及补阳还五汤的调控机制进行探讨，为治疗老年性心衰找寻新的靶点，为补阳还五汤的临床应用提供科学依据。

Imbalance of sphingolipid metabolism is involved in the occurrence and development of aging and heart failure after myocardial infarction. Des1 is the key enzyme in de novo sphingolipid synthesis pathway leading sphingolipid metabolism, but its role in ventricular remodeling after myocardial infarction in the aged is still unclear. Deficiency of Qi and blood stasis is one of the main pathogenesis of age related ventricular remodeling after myocardial infarction. We have previously confirmed that Buyang Huanwu Decoction, the representative prescription of Qi-tonifying and blood-activating therapy, has the effect of anti-ventricular remodeling after myocardial infarction. Based on previous researches, this project puts forward the following hypothesis: Sphingolipid metabolism would be a possible mechanism for the development of ventricular remodeling to heart failure after myocardial infarction in the aged. Des1 and the sphingolipid de novo synthesis pathway would be potential targets involving in sphingolipid metabolism. Buyang Huanwu Decoction might modulate Des1 to rebalance sphingolipid metabolism and reverse ventricular remodeling after myocardial infarction in old people. We will ligate coronary artery of the senescence accelerated mouse/prone (Samp8) to make the animal model of age related ventricular remodeling after myocardial infarction, and detect index of sphingolipid metabolism by sphingolipidomics and transcriptomics. The research is expected to contribute to the exploration of new therapeutic targets and effective drugs, and to enrich the efficacy mechanism of traditional Chinese medicine.