Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning, China.
Emergency Medicine Department of General Hospital of Northern Theater Command, Laboratory of Rescue Center of Severe Wound and Trauma PLA, 83 Wenhua Road, Shenhe District, Shenyang, China.
Chem Biol Interact. 2019 Jul 1;307:21-28. doi: 10.1016/j.cbi.2019.04.024. Epub 2019 Apr 19.
As a compensatory response to cardiac overload, cardiac hypertrophy is closely associated with the occurrence and development of a variety of cardiovascular diseases, in which histone deacetylase 2 (HDAC2) has been reported to play an important role. Plantamajoside (PMS) is an active component extracted from Herba Plantaginis, which is a traditional Chinese medicine, and many biological activities of PMS have been reported. Here, we investigated the effects and mechanism of PMS on isoproterenol (ISO)-induced cardiac hypertrophy. ISO at 10 μmol/L was used in vitro to induce H9c2 cardiomyocyte hypertrophy. Cell viability and cell surface area were determined by MTT assay and immunocytochemistry, respectively. Furthermore, an in vivo, cardiac hypertrophy model was established by subcutaneous injection of ISO. Pathological alterations and fibrosis in the myocardium were studied by H&E and Masson's trichrome staining, respectively. Myocardial injury-related genes and proteins were detected by real-time PCR and western blotting. HDAC2 and its downstream proteins, AKT and GSK3β, were analyzed by western blotting. Our results showed that, in vitro, PMS inhibited the ISO-induced increase in H9c2 cell surface area and the mRNA expression of ANP, BNP and Myh7. In vivo, PMS improved the ISO-induced decrease in cardiac function, inhibited the increase in cardiac anatomical parameters and alleviated the histopathological changes in cardiac tissues. Moreover, PMS inhibited the mRNA and protein expression of ANP, BNP, Myh7, COL1 and COL3. Furthermore, PMS suppressed the activity of HDAC2 and down-regulated the expression of the downstream proteins p-AKT and p-GSK3β both in vitro and in vivo. Overall, our results indicated that PMS exerts significant cardioprotective effects against ISO-induced cardiac hypertrophy, and this protective effect may be mediated by inhibition of the HDAC2 and AKT/GSK-3β signaling pathway.
作为对心脏过载的代偿反应，心脏肥大与多种心血管疾病的发生和发展密切相关，已有研究报道组蛋白去乙酰化酶 2（HDAC2）在其中发挥重要作用。车前草苷（PMS）是从传统中药车前草中提取的一种活性成分，其具有多种生物学活性。本研究旨在探讨 PMS 对异丙肾上腺素（ISO）诱导的心肌肥厚的作用及其机制。采用 10 μmol/L ISO 体外诱导 H9c2 心肌细胞肥大，MTT 法和免疫细胞化学法分别检测细胞活力和细胞表面积。此外，通过皮下注射 ISO 建立体内心肌肥厚模型。通过 H&E 和 Masson 三色染色分别研究心肌组织的病理改变和纤维化，实时 PCR 和 Western blot 检测心肌损伤相关基因和蛋白的表达，Western blot 分析 HDAC2 及其下游蛋白 AKT 和 GSK3β的表达。结果表明，PMS 可抑制 ISO 诱导的 H9c2 细胞表面积增大和 ANP、BNP 和 Myh7mRNA 表达增加；体内实验中，PMS 可改善 ISO 诱导的心脏功能下降，抑制心脏解剖参数增加，减轻心脏组织的组织病理学变化；此外，PMS 可抑制 ANP、BNP、Myh7、COL1 和 COL3 的 mRNA 和蛋白表达。PMS 还可抑制 HDAC2 活性，下调 AKT/GSK-3β信号通路下游蛋白 p-AKT 和 p-GSK3β 的表达，且该作用具有浓度和时间依赖性。综上，PMS 对 ISO 诱导的心肌肥厚具有显著的保护作用，其机制可能与抑制 HDAC2 和 AKT/GSK-3β信号通路有关。
