基于Galectin-3介导的TGF-β1/Smad3通路探讨参连复脉颗粒干预炎症-心房纤维化-房颤作用机制

Atrial fibrillation is the key and difficult point in the prevention and treatment of cardiovascular field. SLFM Granules replenishing qi and activating blood circulation, clearing the heart and removing blood stasis, and revitalizing the mind and calming the nerves, previous studies have shown that SLFM is effective for treating arrhythmia, and the constituent drugs can reduce inflammation and inhibit atrial fibrosis. A large number of modern studies have shown that galectin-3 is an inflammatory factor closely related to the occurrence, development and outcome of atrial fibrillation. It can regulate atrial fibrosis by activating the TGF-β1/Smad3 pathway. It was suggested that "SLFM Granules may play a role in delaying or even blocking the occurrence and development of atrial fibrillation by inhibiting Galectin-3 mediated pro-inflammatory and atrial fibrosis responses. This effect may be based on TGF-β1/Smad3.". The study proposed to use SLFM Granules as an intervention measure, combining in vitro and in vivo studies to investigate its effects on atrial inflammatory response, atrial fibrosis, atrial fibrillation, atrial effective refractory period, Galectin-3, and TGF-β1, Smad3 protein and its mRNA expression levels and other indicators. It is expected to provide scientific evidence for SLFM Granules on preventing and treating atrial fibrillation, for further elucidating the anti-arrhythmic pharmacological effects of Chinese medicine, and to provide new treatment strategies for atrial fibrillation.

房颤为目前心血管领域防治的重点与难点。参连复脉颗粒益气活血、清心化痰、宁心安神，前期研究表明治疗心律失常有效，组成药物可减轻炎症反应、抑制心房纤维化。现代大量研究表明半乳糖凝集素-3是与房颤发生、发展及转归密切相关的炎症因子，可通过激活TGF-β1/Smad3通路调控心房纤维化。由此提出“参连复脉颗粒可能通过抑制Galectin-3介导的促炎、促心房纤维化反应，起到延缓甚至阻断房颤发生发展的作用，这种作用可能基于TGF-β1/Smad3通路的调节”假说。研究拟以参连复脉颗粒为干预措施，在体与离体研究相结合，考察其对心房炎症反应、心房纤维化、房颤诱发率、心房有效不应期、Galectin-3、TGF-β1、Smad3蛋白及其mRNA表达水平等指标的影响。预期将为参连复脉颗粒防治房颤提供科学依据，为进一步阐释中药抗心律失常药理作用提供实验证据，为房颤患者提供新的治疗策略。

本研究获得了以下结果：1.参连复脉颗粒能改善自发性高血压大鼠心房结构重构，对心房电重构及房颤易感性有一定抑制作用；2.参连复脉颗粒改善自发性高血压大鼠心房结构重构的机制可能和调控ERK1/2及TGF-β1/Smad3信号通路有关；3.参连复脉颗粒含药血清可促进内毒素诱导的RAW264.7细胞向M2型极化，抑制LPS诱导的炎症反应，但是否基于Galectin-3介导的TGF-β1/Smad3信号通路起到抗早期纤维化的作用有待于进一步研究；4.黄连具有治疗房颤的药效物质基础与分子生物学机制，其有效成分可能是盐酸小檗碱；5.盐酸小檗碱可促进内毒素诱导的RAW264.7细胞向M2型极化，抑制LPS诱导的炎症反应，但是否基于Galectin-3介导的TGF-β1/Smad3信号通路起到抗早期纤维化的作用有待于进一步研究。课题基本验证了“参连复脉颗粒可能通过抑制Galectin-3介导的促炎、促心房纤维化反应，起到延缓甚至阻断房颤发生发展的作用，这种作用可能基于TGF-β1/Smad3通路的调节”假说的科学性，为参连复脉颗粒防治房颤提供了科学依据，阐明了其益气活血、宁心安神功效的物质基础和作用机理，为进一步阐释中药抗心律失常药理作用提供实验证据，为房颤患者提供新的治疗策略。