School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China.
Biomed Pharmacother. 2020 Oct;130:110522. doi: 10.1016/j.biopha.2020.110522. Epub 2020 Jul 28.
Myocardial fibrosis is well-known to be the aberrant deposition of extracellular matrix (ECM), which may cause cardiac dysfunction, morbidity, and death. Traditional Chinese medicine formula Si-Miao-Yong-An Decoction (SMYAD), which is used clinically in cardiovascular diseases has been recently reported to able to resist myocardial fibrosis. The anti-fibrosis effects of SMYAD have been evaluated; however, its intricate mechanisms remain to be clarified. Here, we found that SMYAD treatment reduced the fibrosis injury and collagen fiber deposition that could improve cardiac function in isoprenaline (ISO)-induced fibrosis rat models. Combined with our systematic RNA-seq data of SMYAD treatment, we demonstrated that the remarkable up-regulation or down-regulation of several genes were closely related to the functional enrichment of TGF-β and AMPK pathways that were involved in myocardial fibrosis. Accordingly, we further explored the molecular mechanisms of SMYAD were mainly caused by AMPK activation and thereby suppressing its downstream Akt/mTOR and TGF-β/SMAD3 pathways. Moreover, we showed that the ECM deposition and secretion process were attenuated, suggesting that the fibrosis pathological features are changed. Interestingly, we found the similar AMPK-driven pathways in NIH-3T3 mouse fibroblasts treated with ISO. Taken together, these results demonstrate that SMYAD may be a new candidate agent by regulating AMPK-driven Akt/mTOR and TGF-β/SMAD3 pathways for potential therapeutic implications of myocardial fibrosis.
心肌纤维化是细胞外基质（ECM）异常沉积的结果，可导致心脏功能障碍、发病和死亡。临床上用于心血管疾病的中药方剂四妙勇安汤（SMYAD）最近被报道能够抵抗心肌纤维化。SMYAD 的抗纤维化作用已经得到评估，但它的复杂机制仍需阐明。在这里，我们发现 SMYAD 治疗可减少纤维化损伤和胶原纤维沉积，从而改善异丙肾上腺素（ISO）诱导的纤维化大鼠模型中的心脏功能。结合我们对 SMYAD 治疗的系统 RNA-seq 数据，我们证明了几个基因的显著上调或下调与 TGF-β 和 AMPK 途径的功能富集密切相关，这些途径参与了心肌纤维化。因此，我们进一步探讨了 SMYAD 的分子机制主要是通过激活 AMPK 来抑制其下游 Akt/mTOR 和 TGF-β/SMAD3 途径。此外，我们表明 ECM 的沉积和分泌过程被减弱，表明纤维化的病理特征发生了变化。有趣的是，我们发现 ISO 处理的 NIH-3T3 小鼠成纤维细胞中存在类似的 AMPK 驱动途径。综上所述，这些结果表明，SMYAD 可能是一种通过调节 AMPK 驱动的 Akt/mTOR 和 TGF-β/SMAD3 途径来治疗心肌纤维化的新候选药物。
