Intensive Care Research Team of Traditional Chinese Medicine, Guangdong Province Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
Chin J Integr Med. 2023 Jul;29(7):600-607. doi: 10.1007/s11655-023-3633-0. Epub 2023 Mar 26.
To investigate the protective mechanisms of Chinese medicine Shexiang Tongxin Dropping Pills (STDP) on heart failure (HF).
Isoproterenol (ISO)-induced HF rat model and angiotensin II (Ang II)-induced neonatal rat cardiac fibroblast (CFs) model were used in the present study. HF rats were treated with and without STDP (3 g/kg). RNA-seq was performed to identify differentially expressed genes (DEGs). Cardiac function was evaluated by echocardiography. Hematoxylin and eosin and Masson's stainings were taken to assess cardiac fibrosis. The levels of collagen I (Col I) and collagen III (Col III) were detected by immunohistochemical staining. CCK8 kit and transwell assay were implemented to test the CFs' proliferative and migratory activity, respectively. The protein expressions of α-smooth muscle actin (α-SMA), matrix metalloproteinase-2 (MMP-2), MMP-9, Col I, and Col III were detected by Western blotting.
The results of RNA-seq analysis showed that STDP exerted its pharmacological effects on HF via multiple signaling pathways, such as the extracellular matrix (ECM)-receptor interaction, cell cycle, and B cell receptor interaction. Results from in vivo experiments demonstrated that STDP treatment reversed declines in cardiac function, inhibiting myocardial fibrosis, and reversing increases in Col I and Col III expression levels in the hearts of HF rats. Moreover, STDP (6, 9 mg/mL) inhibited the proliferation and migration of CFs exposed to Ang II in vitro (P<0.05). The activation of collagen synthesis and myofibroblast generation were markedly suppressed by STDP, also the synthesis of MMP-2 and MMP-9, as well as ECM components Col I, Col III, and α-SMA were decreased in Ang II-induced neonatal rats' CFs.
STDP had anti-fibrotic effects in HF, which might be caused by the modulation of ECM-receptor interaction pathways. Through the management of cardiac fibrosis, STDP may be a compelling candidate for improving prognosis of HF.
探讨麝香通心滴丸（STDP）对心力衰竭（HF）的保护机制。
本研究采用异丙肾上腺素（ISO）诱导的 HF 大鼠模型和血管紧张素 II（Ang II）诱导的新生大鼠心肌成纤维细胞（CFs）模型。HF 大鼠给予或不给予 STDP（3 g/kg）治疗。采用 RNA-seq 鉴定差异表达基因（DEGs）。通过超声心动图评估心功能。苏木精和伊红及 Masson 染色评估心肌纤维化。免疫组织化学染色检测胶原 I（Col I）和胶原 III（Col III）水平。CCK8 试剂盒和 Transwell 测定分别用于检测 CFs 的增殖和迁移活性。Western blot 检测α-平滑肌肌动蛋白（α-SMA）、基质金属蛋白酶-2（MMP-2）、MMP-9、Col I 和 Col III 的蛋白表达。
RNA-seq 分析结果表明，STDP 通过细胞外基质（ECM）-受体相互作用、细胞周期和 B 细胞受体相互作用等多种信号通路发挥对 HF 的药理作用。体内实验结果表明，STDP 治疗可逆转 HF 大鼠心功能下降，抑制心肌纤维化，并逆转 HF 大鼠心脏中 Col I 和 Col III 表达水平的升高。此外，STDP（6、9 mg/mL）抑制 Ang II 体外诱导的 CFs 的增殖和迁移（P<0.05）。STDP 显著抑制胶原合成和肌成纤维细胞生成的激活，同时降低 Ang II 诱导的新生大鼠 CFs 中 MMP-2 和 MMP-9 以及 ECM 成分 Col I、Col III 和α-SMA 的合成。
STDP 对 HF 具有抗纤维化作用，这可能是通过调节 ECM-受体相互作用途径实现的。通过对心肌纤维化的管理，STDP 可能成为改善 HF 预后的有吸引力的候选药物。
