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Archive > Volume 17 Issue 1 > 2025,17(1):148-155. DOI:https://doi.org/10.1016/j.chmed.2023.12.004 Prev Next

四逆湯通過花生四烯酸代謝通路改善心肌梗死大鼠炎癥反應(yīng)

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Sini decoction alleviates inflammation injury after myocardial infarction through regulating arachidonic acid metabolism

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    摘要:
    目的：從花生四烯酸代謝通路闡釋四逆湯改善心肌梗死大鼠炎癥反應(yīng)的作用機(jī)制。方法：首先采用脂多糖（LPS）誘導(dǎo)巨噬細(xì)胞RAW264.7炎癥損傷模型，以塞來昔布（Celecoxib）作為陽性藥，通過對細(xì)胞上清液中釋放的炎性細(xì)胞因子NO、LDH進(jìn)行檢測，以及TNF-α、IL-6、p-NF-κB和COX-2的蛋白分析，考察四逆湯對LPS誘導(dǎo)巨噬細(xì)胞的抗炎機(jī)制。在此基礎(chǔ)上，采用LPS刺激巨噬細(xì)胞產(chǎn)生的上清液作為條件培養(yǎng)基（CM）構(gòu)建H9c2心肌細(xì)胞炎癥損傷模型，通過CCK-8實(shí)驗(yàn)、Griess法檢測NO的釋放及TNF-α、IL-6、Bax、Bcl-2、Cleaved-caspase-3、p-NF-κB 和COX-2的蛋白表達(dá)，考察四逆湯對心肌細(xì)胞炎癥損傷的保護(hù)作用。最后，通過冠狀動(dòng)脈左前降支結(jié)扎法構(gòu)建大鼠心肌梗死模型，44只SD大鼠隨機(jī)分為假手術(shù)組（n=7）、心肌梗死組（n=11）、四逆湯低劑量組（10 g/kg，n=9）和四逆湯高劑量組（10 g/kg，n=9）、塞來昔布組（30 mg/kg，n=8），給藥組每天灌胃1次，假手術(shù)組和心肌梗死組給予等量生理鹽水。4周后進(jìn)行超聲心動(dòng)圖檢測心功能，H&E染色和Masson染色檢測心臟病理變化，血清生化檢測CK、CK-MB和LDH水平，Western blot檢測花生四烯酸代謝途徑中的關(guān)鍵酶sPLA2、COX-1、COX-2、5-LOX和15-LOX的表達(dá)。結(jié)果：四逆湯能有效抑制LPS誘導(dǎo)巨噬細(xì)胞RAW264.7釋放NO，Western blot結(jié)果顯示四逆湯能夠有效抑制TNF-α、IL-6、p-NF-κB和COX-2蛋白表達(dá)。在CM構(gòu)建H9c2心肌細(xì)胞炎癥損傷模型中，與模型組相比，四逆湯組可以提高心肌細(xì)胞活力，減少NO 、TNF-α和IL-6的釋放，抑制Bax、Bcl-2、Cleaved-caspase-3、p-NF-κB 和COX-2蛋白的表達(dá)。體內(nèi)動(dòng)物水平研究表明四逆湯可顯著改善心肌梗死大鼠的心功能、心肌炎性細(xì)胞的浸潤和纖維化程度，減少CK、CK-MB和LDH的釋放，抑制花生四烯酸代謝途徑中的關(guān)鍵酶sPLA2、COX-1、COX-2、5-LOX和15-LOX的表達(dá)。結(jié)論：四逆湯能夠有效改善心肌梗死大鼠的心功能，抑制花生四烯酸代謝通路中關(guān)鍵蛋白的表達(dá)，減輕心肌細(xì)胞損傷，改善炎癥反應(yīng)，從而發(fā)揮抗心肌炎癥損傷的作用。

    Abstract:
    Objective: Myocardial inflammation during myocardial infarction (MI) could be inhibited by regulating arachidonic acid (AA) metabolism. Recent studies demonstrated that Sini Decoction (SND) was identified to be an effective prescription for treating heart failure (HF) caused by MI. But the anti-inflammatory mechanism of SND remained unclear. The work was designed to investigate the anti-inflammatory mechanism of SND through the AA metabolism pathway in vitro and in vivo experiments. Methods: An inflammatory injury model of H9c2 cells was established by lipopolysaccharide (LPS)-stimulated macrophage-conditioned medium (CM). The MI model was built by the ligation of left anterior descending (LAD) branch of coronary artery in rat. Meanwhile, the rats were divided into five groups: sham group, MI group, MI + Celecoxib group, MI + low-dose SND group (SND-L) and MI + high-dose SND group (SND-H). Cardiac function, histopathological changes and serum cytokines were examined four weeks later. Western blot analysis was conducted to verify the key enzymes levels in the AA metabolic pathway, including phospholipase A2 (PLA2), cyclooxygenases (COXs) and lipoxygenases (LOXs). Results: These in vivo results demonstrated that SND could improve the cardiac function and pathological changes of rats with MI, and regulate the key inflammatory molecules in the AA metabolism pathway, including sPLA2, COX-1, COX-2, 5-LOX and 15-LOX. In vitro, SND could decrease the release of proinflammatory cytokines including TNF-a and IL-6 and inhibit cell apoptosis in CM-induced H9c2 cells. Moreover, SND could protect H9c2 cells from the damage of CM by regulating nuclear factor kappa-B (NF-jB) signal pathway and the expression of COX-2. Conclusion: SND may be a drug candidate for anti-inflammatory treatment during MI by regulating the multiple targets in the AA metabolism pathway.

    關(guān)鍵詞:
    抗炎;花生四烯酸代謝通路;條件培養(yǎng)基;心肌梗死;四逆湯

    Keywords:


    Project Supported:
    This work was supported by the National Natural Science Foundation of China (No. 82173772, 82003916, 82204586, 81773677), Shaanxi Provincial Key Research and Development Program (No.2022ZDLSF05-06), the Open Project Program of MOE Key Laboratory of Drug Quality Control and Pharmacovigilance (No.DQCP20/21PQ07), and the innovation Capability Support Program of Shaanxi (No. 2020TD-041).

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