( )-Isobicyclogermacrenal and spathulenol from Aristolochia yunnanensis alleviate cardiac fibrosis by inhibiting transforming growth factor beta/small mother against decapentaplegic signaling pathway
( )-Isobicyclogermacrenal and spathulenol from Aristolochia yunnanensis alleviate cardiac fibrosis by inhibiting transforming growth factor beta/small mother against decapentaplegic signaling pathway
复制标题
云南马兜铃中的 ( )-异双环锗烯醛和匙叶菊烯醇通过抑制转化生长因子β/小母体对去甲麻痹信号通路的作用减轻心脏纤维化
DOI：
10.1002/ptr.6219
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发表时间：
2019
影响因子：
7.2
通讯作者：
Yin Sheng
中科院分区：
文献类型：
--
作者：
Lou Lan Lan;Li Wei;Zhou Bin Hua;Chen Lin;Weng Han Zhuang;Zou Yi Hong;Tang Gui Hua;Bu Xian Zhang;Yin Sheng
在许多心脏病理生理条件下，心脏纤维化都会导致收缩和舒张期功能障碍。抗纤维化治疗可能是遏制许多与纤维化相关的心脏疾病的关键策略。在我们之前的研究中，我们对中药云南马兜铃的乙酸乙酯提取物进行了研究。在体内外均发现对心肌纤维化有治疗作用。然而，导致粗提物活性的确切化学物质及其机制尚未阐明。本研究从该活性提取物中分离得到10个倍半萜类化合物(1-10)，并在转化生长因子β-1(转化生长因子-β-1)刺激的心肌成纤维细胞和NIH3T3纤维化模型上系统评价了它们的抗纤维化作用。(+)-异双环大肾素(1)和刺五味子酚(2)为主要活性成分，比天然抗纤维化药物氧化苦参碱更有效。化合物1和2可抑制转化生长因子β1诱导的心脏成纤维细胞的增殖，并通过下调纤维化生物标志物纤维连接蛋白和α-平滑肌肌动蛋白的基因表达而抑制其表达。机制研究表明，1和2可抑制转化生长因子βI型受体的磷酸化，导致下游Smad2/3的磷酸化水平降低，从而阻断Smad2/3在转化生长因子β/Smad2信号通路中的核转位。这些发现表明，1和2可能是开发抗心脏纤维化药物的有希望的天然先导。
Cardiac fibrosis contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. Antifibrotic therapies are likely to be a crucial strategy in curbing many fibrosis‐related cardiac diseases. In our previous study, an ethyl acetate extract of a traditional Chinese medicineAristolochia yunnanensisFranch. was found to have a therapeutic effect on myocardial fibrosis in vitro and in vivo. However, the exact chemicals and their mechanisms responsible for the activity of the crude extract have not been illustrated yet. In the current study, 10 sesquiterpenoids (1–10) were isolated from the active extract, and their antifibrotic effects were systematically evaluated in transforming growth factor β 1 (TGFβ1)‐stimulated cardiac fibroblasts and NIH3T3 fibrosis models. (+)‐Isobicyclogermacrenal (1) and spathulenol (2) were identified as the main active components, being more potent than the well‐known natural antifibrotic agent oxymatrine. Compounds1and2could inhibit the TGFβ1‐induced cardiac fibroblasts proliferation and suppress the expression of the fibrosis biomarkers fibronectin and α‐smooth muscle actin via down‐regulation of their mRNA levels. The mechanism study revealed that1and2could inhibit the phosphorylation of TGFβ type I receptor, leading to the decrease of the phosphorylation levels of downstream Smad2/3, then consequently blocking the nuclear translocation of Smad2/3 in the TGFβ/Smad signaling pathway. These findings suggest that1and2may serve as promising natural leads for the development of anticardiac fibrosis drugs.