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Abstract：
Background and objectives Ginsenoside Re (Re), a protopanaxatriol-type saponin extracted from ginseng, is known to have potential cardioprotective effects; however, the mechanisms of Re in improving cardiac hypertrophy have not been fully elucidated. This study aimed to investigate the therapeutic effects and underlying mechanism of Re on isoproterenol (ISO)-induced cardiac hypertrophy in vivo and in vitro. Methods Rats were intraperitoneally injected with ISO 30 mg/kg thrice daily for 14 consecutive days to induce cardiac hypertrophy, and these rats were treated with atorvastatin (ATC, 20 mg/kg) or Re (20 mg/kg or 40 mg/kg) once daily for three days in advance until the end of the experiment. Heart weight index, hematoxylin and eosin staining, and hypertrophy-related fetal gene expression were measured to evaluate the effect of Re on cardiac hypertrophy in vivo. Meanwhile, the rat H9c2 cardiomyocyte hypertrophy model was induced by ISO 10 μM for 24 hours. Cell surface area and hypertrophy-related fetal gene expression were determined to assess the effect of Re on ISO-induced cardiomyocyte hypertrophy in vitro. The levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in both serum and cardiomyocytes were detected by enzymatic colorimetric assays. Furthermore, we chose cholesteryl ester transfer protein (CETP) as a target to explore the influence of Re on CETP expression in vivo and in vitro through real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay. Results Intraperitoneal administration of ISO into rats resulted in increases in cross-sectional cardiomyocyte area, the ratio of heart weight to body weight, the ratio of left ventricular weight to body weight, and the ratio of right ventricular weight to body weight, as well as reactivation of fetal genes; however, treatment with Re or ATC ameliorated most of these hypertrophic responses. Similarly, Re pronouncedly alleviated ISO-induced cardiomyocyte hypertrophy, as evidenced by a decreased cell surface area and downregulation of fetal genes. Moreover, our in vivo and in vitro data revealed that Re reduced TC, TG, and LDL-C levels, and enhanced HDL-C levels. Re improved cardiac hypertrophy mainly associated with the inhibition of mRNA level and protein expression of CETP, to an extent comparable to that of the classical CETP inhibitor, anacetrapib. Conclusions Our research found that CETP inhibition contributes to the protection of Re against ISO-induced cardiac hypertrophy, which provides evidence for the application of Re for cardiovascular disease treatments.
摘要：
背景和目标人参皂苷Re（Re），从人参中提取的原参三醇型皂苷，已知具有潜在的心脏保护作用；然而，Re改善心肌肥厚的机制尚未完全阐明。本研究旨在探讨Re对异丙肾上腺素(ISO)诱导的心肌肥厚的体内外治疗作用及其机制。方法大鼠腹腔注射ISO30mg/kg,每日3次,连续14天,诱导心肌肥厚,这些大鼠用阿托伐他汀(ATC，20mg/kg）或Re（20mg/kg或40mg/kg）每天一次，提前三天，直到实验结束。心脏体重指数,苏木精和伊红染色，测量与肥大相关的胎儿基因表达以评估Re对体内心肌肥大的影响。同时,ISO10μM诱导大鼠H9c2心肌细胞肥大模型24小时。测定细胞表面积和肥大相关的胎儿基因表达以评估Re对体外ISO诱导的心肌细胞肥大的影响。总胆固醇（TC）的水平，甘油三酯（TG），低密度脂蛋白胆固醇（LDL-C），通过酶比色法检测血清和心肌细胞中的高密度脂蛋白胆固醇（HDL-C）。此外，我们选择胆固醇酯转运蛋白(CETP)为靶点,通过实时聚合酶链反应,探讨Re对CETP体内外表达的影响,westernblot,和酶联免疫吸附测定。结果大鼠腹腔注射ISO导致心肌细胞横截面面积增加，心脏重量与体重的比率，左心室重量与体重之比，以及右心室重量与体重的比率，以及胎儿基因的重新激活；然而，用Re或ATC治疗改善了大多数这些肥大反应。同样，重新明确缓解ISO诱导的心肌细胞肥大，细胞表面积减少和胎儿基因下调证明了这一点。此外，我们的体内和体外数据显示Re降低了TC，TG,和LDL-C水平，和增强的HDL-C水平。再改善心肌肥厚主要与抑制CETPmRNA和蛋白表达有关,与经典的CETP抑制剂相当，anacetrapib.结论我们的研究发现，抑制CETP有助于保护Re抵抗ISO诱导的心肌肥厚，这为Re在心血管疾病治疗中的应用提供了证据。
