Lingguizhugan decoction attenuates doxorubicin-induced heart failure in rats by improving TT-SR microstructural remodeling
Lingguizhugan decoction attenuates doxorubicin-induced heart failure in rats by improving TT-SR microstructural remodeling
复制标题
苓桂术甘汤通过改善TT-SR微结构重塑减轻阿霉素诱导的大鼠心力衰竭
DOI：
10.1186/s12906-019-2771-6
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发表时间：
2019-12-11
影响因子：
--
通讯作者：
Gao, Yongxiang
中科院分区：
文献类型：
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作者：
Li, Xueping;Xu, Guangmin;Gao, Yongxiang
灵归柱肝汤是一种古老的中草药配方，在东亚被用来治疗心血管疾病。我们在心力衰竭（HF）动物模型中研究了LGZG是否具有保护活性及其作用机制。方法采用多柔比星（DOX）腹腔注射8次（累积剂量16 mg/kg），连续4周建立HF大鼠模型。随后，以5、10、15 mL/kg/d剂量给药，每天1次，连续4周。通过观察大鼠体重、心重指数（HWI）、心重/胫长比（HW/TL）及血清BNP水平，评价LGZG对HF的影响。超声心动图观察心功能，H&E染色观察心肌形态。透射电镜观察心肌超微结构及t小管-肌浆网（TT-SR）连接。Western blotting检测JP-2蛋白水平。采用定量RT-PCR检测各组CACNA1S、RyR2 mRNA水平及microRNA-24 （miR-24）水平。结果DOX治疗4周后，大鼠出现心脏损伤，与对照组相比，BNP水平显著升高（169.6±29.6 pg/mL vs 80.1±9.8 pg/mL，P< 0.001）。相反，LGZG显著降低BNP水平（93.8±17.9 pg/mL，P< 0.001），特别是在最高剂量时。用DOX治疗的大鼠出现心功能障碍，其特征是左心室射血分数与对照组相比明显下降（58.5±8.7%比88.7±4.0%；P< 0.001）。地高辛和LGZG改善了心功能障碍（分别为79.6±6.1%、69.2±2.5%），保持了左室射血分数（分别为77.9±5.1、80.5±4.9，P< 0.01）。LGZG还能改善LVEDD、LVESD和FS，消除心室肥厚，HWI和HW/TL比值降低。LGZG能减轻心肌形态学异常和线粒体损伤。此外，与dox处理的大鼠相比，高剂量LGZG显著下调miR-24的表达（倍数变化1.4比3.4，P< 0.001），但上调JP-2的表达并拮抗dox诱导的t小管TT-SR微结构重塑。这些活性改善了周期性Ca2+瞬态和细胞收缩，这可能是LGZG对HF有益作用的基础。结论slgzg对dox致大鼠HF有一定的抑制作用，其作用机制可能与改善TT-SR微结构重塑有关。
BackgroundLingguizhugan decoction (LGZG), an ancient Chinese herbal formula, has been used to treat cardiovascular diseases in eastern Asia. We investigated whether LGZG has protective activity and the mechanism underlying its effect in an animal model of heart failure (HF).MethodsA rat model of HF was established by administering eight intraperitoneal injections of doxorubicin (DOX) (cumulative dose of 16 mg/kg) over a 4-week period. Subsequently, LGZG at 5, 10, and 15 mL/kg/d was administered to the rats intragastrically once daily for 4 weeks. The body weight, heart weight index (HWI), heart weight/tibia length ratio (HW/TL), and serum BNP level were investigated to assess the effect of LGZG on HF. Echocardiography was performed to investigate cardiac function, and H&E staining to visualize myocardial morphology. Myocardial ultrastructure and T-tubule-sarcoplasmic reticulum (TT-SR) junctions were observed by transmission electron microscopy. The JP-2 protein level was determined by Western blotting. The mRNA level of CACNA1S and RyR2 and the microRNA-24 (miR-24) level were assayed by quantitative RT-PCR.ResultsFour weeks after DOX treatment, rats developed cardiac damage and exhibited a significantly increased BNP level compared with the control rats (169.6 ± 29.6 pg/mL versus 80.1 ± 9.8 pg/mL,P< 0.001). Conversely, LGZG, especially at the highest dose, markedly reduced the BNP level (93.8 ± 17.9 pg/mL,P< 0.001). Rats treated with DOX developed cardiac dysfunction, characterized by a strong decrease in left ventricular ejection fraction compared with the control (58.5 ± 8.7% versus 88.7 ± 4.0%;P< 0.001). Digoxin and LGZG improved cardiac dysfunction (79.6 ± 6.1%, 69.2 ± 2.5%, respectively) and preserved the left ventricular ejection fraction (77.9 ± 5.1, and 80.5 ± 4.9, respectively,P< 0.01). LGZG also improved the LVEDD, LVESD, and FS and eliminated ventricular hypertrophy, as indicated by decreased HWI and HW/TL ratio. LGZG attenuated morphological abnormalities and mitochondrial damage in the myocardium. In addition, a high dose of LGZG significantly downregulated the expression of miR-24 compared with that in DOX-treated rats (fold change 1.4 versus 3.4,P< 0.001), but upregulated the expression of JP-2 and antagonized DOX-induced T-tubule TT-SR microstructural remodeling. These activities improved periodic Ca2+transients and cell contraction, which may underly the beneficial effect of LGZG on HF.ConclusionsLGZG exerted beneficial effects on DOX-induced HF in rats, which were mediated in part by improved TT-SR microstructural remodeling.