荭草素钠通过结合 MMP2 和 p38 抑制心肌纤维化从而减轻异丙肾上腺素诱导的心力衰竭。
Sodium houttuyfonate against cardiac fibrosis attenuates isoproterenol-induced heart failure by binding to MMP2 and p38.
机构信息
Department of Physiology, Basic Medical School, Xuzhou Medical University, Xuzhou 221004, China.
Department of Physiology, Basic Medical School, Xuzhou Medical University, Xuzhou 221004, China; School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
出版信息
Phytomedicine. 2023 Jan;109:154590. doi: 10.1016/j.phymed.2022.154590. Epub 2022 Dec 5.
BACKGROUND
Heart failure (HF), caused by stress cardiomyopathy, is a major cause of mortality. Cardiac fibrosis is an essential structural remodeling associated with HF; therefore, preventing cardiac fibrosis is crucial to decelerating the progression of HF. Sodium houttuyfonate (SH), an extract of Houttuynia cordata, has a potent therapeutic effect on hypoxic cardiomyocytes in a myocardial infarction model.
PURPOSE
To investigate the preventative and therapeutic effects of SH during isoproterenol (ISO)-induced HF and explore the pharmacological mechanism of SH in alleviating HF.
METHODS
We analyzed the overlapping target genes between SH and cardiac fibrosis or HF using a network pharmacology analytical method. We verified the suppressive effect of SH on ISO-induced proliferation and activation of cardiac fibroblasts by immunohistochemical staining and histological analysis in an isoproterenol-induced HF mouse model. Additionally, we investigated the effect of SH by evaluating fibrosis and cardiac remodeling markers. To further decipher the pharmacological mechanism of SH against cardiac fibrosis and HF, we performed a molecular docking analysis between SH and hub common target genes.
RESULTS
There were 20 overlapping target genes between SH and cardiac fibrosis and 32 overlapping target genes between SH and HF. The 16 common target genes of SH against cardiac fibrosis and HF included MMP2 (matrix metalloproteinase 2), and p38. SH significantly inhibited the ISO- or TGF-β-induced expression of Col1α (collagen 1), α-SMA (smooth muscle actin), MMP2, TIMP2 (tissue inhibitor of metalloproteinase 2), TGF-β (transforming growth factor), and Smad2 phosphorylation. Moreover, both ISO- and TGF-β-induced p38 phosphorylation was inhibited. Molecular docking analysis showed that SH forms a stable complex with MMP2 and p38.
CONCLUSIONS
In addition to protecting cardiomyocytes, SH directly inhibits cardiac fibroblast activation and proliferation by binding to MMP2 and p38, subsequently delaying cardiac fibrosis and HF progression. Our prevention- and intervention-based approaches in this study showed that SH inhibited the development of stress cardiomyopathy-mediated cardiac fibrosis and HF when SH was administered before or after the initiation of cardiac stress.
背景
应激性心肌病导致的心力衰竭（HF）是死亡的主要原因。心肌纤维化是与 HF 相关的重要结构重塑；因此，预防心肌纤维化对于减缓 HF 的进展至关重要。鱼腥草钠（SH）是鱼腥草的提取物，对心肌梗死模型中的缺氧心肌细胞具有很强的治疗作用。
目的
研究 SH 在异丙肾上腺素（ISO）诱导的 HF 中的预防和治疗作用，并探讨 SH 缓解 HF 的药理机制。
方法
我们使用网络药理学分析方法分析了 SH 与心肌纤维化或 HF 的重叠靶基因。我们通过免疫组织化学染色和组织学分析在 ISO 诱导的 HF 小鼠模型中验证了 SH 对 ISO 诱导的心肌成纤维细胞增殖和激活的抑制作用。此外，我们通过评估纤维化和心脏重塑标志物来研究 SH 的作用。为了进一步阐明 SH 对抗心肌纤维化和 HF 的药理机制，我们对 SH 与枢纽共同靶基因进行了分子对接分析。
结果
SH 与心肌纤维化和 HF 之间有 20 个重叠靶基因，SH 与 HF 之间有 32 个重叠靶基因。SH 针对心肌纤维化和 HF 的 16 个共同靶基因包括 MMP2（基质金属蛋白酶 2）和 p38。SH 显著抑制 ISO 或 TGF-β诱导的 Col1α（胶原蛋白 1）、α-SMA（平滑肌肌动蛋白）、MMP2、TIMP2（金属蛋白酶组织抑制剂 2）、TGF-β（转化生长因子）和 Smad2 磷酸化的表达。此外，ISO 和 TGF-β 诱导的 p38 磷酸化均受到抑制。分子对接分析表明，SH 与 MMP2 和 p38 形成稳定的复合物。
结论
除了保护心肌细胞外，SH 通过与 MMP2 和 p38 结合直接抑制心肌成纤维细胞的激活和增殖，从而延缓心肌纤维化和 HF 的进展。我们在这项研究中采用的预防和干预方法表明，SH 在心脏应激开始前或开始后给予时，可抑制应激性心肌病介导的心脏纤维化和 HF 的发展。
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