活心丸通过抑制Wnt/β-catenin通路阻止急性心肌缺血损伤的机制研究

Acute myocardial infarction (AMI) is a cardiovascular disease that is associated with numerous complications, which can significantly endanger human health. Clinical trials have shown that Huo Xin Wan can be effective in treating coronary heart disease, however, its mechanism has not yet been fully elucidated. Our previous study demonstrated that the activation of Wnt/β-catenin pathway at an early stage of AMI was one of the key causes of oxidative stress injury in cardiomyocytes. Therefore, inhibiting the early activation of Wnt/β-catenin pathway can theoretically prevent further damage to cardiac myocytes at an early stage of AMI. Our preliminary experiments indicate that Huo Xin Wan can significantly inhibits the Wnt/β-catenin pathway, which suggest that “Huo Xin Wan protects AMI injury by inhibiting Wnt/beta-catenin pathway maybe one of the underlying important mechanisms” . We therefore hope to elucidate the precise molecular mechanism of Huo Xin Wan in protecting against AMI injury using AMI animal models, luciferase double-reporter gene assays, Real-time PCRs, Western Blots and immunohistochemical assays both in vitro and in vivo, as well as its therapeutic targets, in order to provide a novel and promising means for the clinical treatment of AMI.

急性心肌缺血(AMI)及其并发症是严重危害人类健康的心血管疾病。临床试验表明活心丸治疗冠心病疗效确切，但作用机制尚未完全阐明。本课题组前期研究发现AMI发生后早期激活的Wnt/β-catenin通路是心肌细胞发生氧化应激损伤的关键原因之一。因此通过靶向抑制AMI发生早期的Wnt/β-catenin通路激活可阻止心肌细胞进一步损伤。预实验显示活心丸可明显抑制Wnt/β-catenin通路，提示“活心丸抑制Wnt/β-catenin通路可能是其保护急性心肌缺血损伤的重要机制”。本课题拟通过急性心肌缺血动物模型，采用荧光素酶双报告基因、Real-time PCR、Western Blot和免疫组化等技术方法阐明活心丸对急性心梗损伤的保护机制，以期深入阐明活心丸治疗急性心肌缺血的分子机制和作用靶点，为临床应用提供理论依据。

急性心肌缺血（AMI）由于其可造成心肌广泛的不可逆损伤，已成为世界范围内导致人类死亡的主要原因之一。因此寻求可有效阻止急性心肌缺血损伤的治疗药物成为临床治疗的迫切需求。急性心肌缺血发生时，Wnt/β-catenin信号通路的异常激活会导致氧自由基（ROS）进一步过量产生，从而恶化心肌缺血损伤。因此通过靶向抑制急性心肌缺血发生早期的Wnt/β-catenin通路激活可阻止心肌细胞进一步损伤。活心丸是一味已经广泛用于治疗冠心病和心绞痛的中成药，但其药理机制尚不明确。我们通过建立心肌梗死小鼠模型探究了活心丸对心肌梗死引起的缺血损伤的保护作用及药理机制。动物实验结果显示活心丸可有效减少梗死面积并显著改善心脏功能。经过进一步体内、外实验验证，我们发现活心丸通过有效抑制Wnt/β-catenin信号异常激活从而阻止其介导的DNA氧化损伤是其药理机制。因此，本研究明确了活心丸对急性心肌缺血损伤的保护作用并阐明了其药理机制，同时还提出了靶向抑制Wnt/β-catenin信号通路是治疗急性缺血性心脏病的新策略。