基于心肌能量代谢重构探讨参附方防治心力衰竭的作用机制研究

Myocardial metabolic remodeling is an important mechanism of pathophysiology of chronic heart failure, involving energy hunger, changes in substrate utilization, mitochondrial dysfunction and insulin resistance and so on. The improvement of cardiac energy metabolism is an important part of delaying heart failure progression. The role of neuroendocrine retarders in the treatment of heart failure has reached the ceiling effect, so it has become a new trend to focuse on the discovery of new targets and the development of natural herbal medicine. Chinese herbs has become one of the important means of comprehensive treatment of heart failure, and heart qi deficiency is one of the basic symptoms of heart failure, myocardial energy metabolism disorder is the pathological basis of cardiac insufficiency, and Chinese herbs for supplementing Qi has the potential function to regulate energy metabolism. The preliminary study showed that Shenfu Formula could improve cardiac function and ventricular remodeling in heart failure model, and was related to the increase of myocardial high-energy phosphate content as well as the improvement of energy reserves and the metabolic state. This study will focus on the key aspects of metabolic remodeling process of myocardial energy metabolism including substrate utilization, insulin resistance, mitochondrial function and otherrelated pathways to explore the characteristics and mechanisms of prevention and treatment of heart failure, so as to perfect the mechanism of Chinese Herbs for Shenfu Formula on the treatment of heart failure, and to provide the new perspective for study on the mechanism of Chinese herbs in treating diseases related to energy metabolic disorder.

心肌代谢重构是慢性心力衰竭病理生理学的重要机制，涉及能量饥饿、底物利用的改变、线粒体功能紊乱和胰岛素抵抗等。针对神经内分泌阻滞剂在心衰治疗中的作用已经达到极限，着眼于新靶点的发现和天然植物药的开发已经成为新的趋势。有效改善心肌能量代谢重构已成为治疗心衰的一个重要环节。中医药已成为心衰综合治疗的重要手段之一，心气虚是其基本症候，心肌能量代谢障碍可能是气虚证的实质，是心功能不全的病理基础，而补气中药具有潜在的纠正能量代谢的功能。前期研究表明具有益气温阳作用的参附方在心衰模型中具有改善心衰后的心脏功能和心室重构，并且与调控线粒体能量代谢密切相关。因此，本研究将从心肌能量代谢重构过程所涉及的关键环节--底物利用、胰岛素抵抗和线粒体功能变化等方面探讨其防治心衰的作用特点和路径，从新的视角完善参附方对心衰治疗作用的机制研究，同时也为中药治疗能量代谢紊乱相关疾病的机制研究提供新的思路。

心脏代谢重塑被认为是心力衰竭(HF)的一个重要标志，而针对能量代谢的策略在治疗心力衰竭方面具有治疗潜力。参附方(S-F)是一种临床常用的标准中药制剂，是治疗HF相关代谢重塑的一种有前景的组合疗法。有效改善心肌能量代谢重构已成为治疗心衰的一个重要环节。在此，我们利用转录组学、蛋白质组学和代谢组学对横主动脉缩窄(TAC)诱导的HF小鼠进行了非靶向多组学分析。综合和通路分析用于揭示与S-F治疗相关的治疗靶点。通过超声心动图、血流动力学、组织病理学和生化检测，验证了S-F的心脏保护作用及其可能机制。因此，S-F 显着减轻了心肌纤维化和肥厚，从而减少了 TAC 小鼠心脏重构过程中心脏功能的丧失。综合组学分析表明，S-F协同调节心脏能量代谢中脂肪酸和葡萄糖的代谢平衡性。我们证实了S-F的治疗作用是通过激活衰竭心脏中的AMP活化蛋白激酶(AMPK)及其下游靶点而发挥的。我们的研究结果表明，S-F通过能量依赖机制激活AMPK相关通路抑制心脏代谢重构。