Salvia miltiorrhiza and Carthamus tinctorius Extract Prevents Cardiac Fibrosis and Dysfunction after Myocardial Infarction by Epigenetically Inhibiting Smad3 Expression
Salvia miltiorrhiza and Carthamus tinctorius Extract Prevents Cardiac Fibrosis and Dysfunction after Myocardial Infarction by Epigenetically Inhibiting Smad3 Expression
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丹参和红花提取物通过表观遗传抑制 Smad3 表达预防心肌梗死后的心脏纤维化和功能障碍
DOI：
10.1155/2019/6479136
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发表时间：
2019-01-01
影响因子：
--
通讯作者：
Zhan, Zhenzhen
中科院分区：
文献类型：
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作者：
Yang, Jing;Wang, Bo;Zhan, Zhenzhen
心肌梗死（MI）后心功能不全的发生率持续增加，尽管治疗的进步。过度的心肌纤维化在不良心脏重构和心功能恶化的发展中起着至关重要的作用。了解纤维化过程的分子和细胞机制并开发有效的治疗方法是非常重要的。丹参和红花提取物（SCE）在中国适用于心绞痛和其他缺血性心血管疾病。SCE可抑制血小板的活化和聚集，通过抑制线粒体通透性转换孔的开放改善ROS诱导的心肌坏死，通过上调血管内皮生长因子（VEGF）的表达促进血管新生。然而，SCE是否对MI后心肌纤维化有影响尚不完全清楚。本研究通过建立小鼠心肌梗死模型，观察SCE对存活率、心功能、心肌纤维化和炎症的影响。采用定量PCR和western blot检测转化生长因子-β（TGF-β）级联反应和体内炎症反应相关基因的表达。此外，还检测了SCE对原代心脏成纤维细胞胶原合成、TGF-β/Smad 3（SMAD family member 3）信号转导和组蛋白甲基化水平的影响。我们发现SCE治疗显著改善MI后小鼠的存活率和左心室功能。SCE治疗可抑制炎症和纤维化，并降低Smad 3的表达。在TGF-β刺激的心脏成纤维细胞中，SCE显著降低胶原、α-平滑肌肌动蛋白（α-SMA）和Smad 3的表达。此外，SCE处理下调心脏成纤维细胞Smad 3启动子区的H3 K4三甲基化（H3 K4 me 3）和H3 K36三甲基化（H3 K36 me 3）水平，导致Smad 3转录抑制。我们的研究结果表明，SCE通过抑制组蛋白Smad 3启动子甲基化及其转录的新机制来防止MI后心肌纤维化和不良重塑。
The incidence of cardiac dysfunction after myocardial infarction (MI) continues to increase despite advances in treatment. Excessive myocardial fibrosis plays a vital role in the development of adverse cardiac remodeling and deterioration of cardiac function. Understanding the molecular and cellular mechanism of the fibrosis process and developing effective therapeutics are of great importance. Salvia miltiorrhiza and Carthamus tinctorius extract (SCE) is indicated for angina pectoris and other ischemic cardiovascular diseases in China. SCE has been shown to inhibit the platelet activation and aggregation, ameliorate ROS-induced myocardial necrosis by inhibiting mitochondrial permeability transition pore opening, and promote angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF). However, whether SCE has effect on cardiac fibrosis after MI is not fully clear. Here, a mouse model of MI was established to observe the effect of SCE upon survival, cardiac function, myocardial fibrosis, and inflammation. Quantitative PCR and western blot assays were used to determine the expression of genes related to transforming growth factor-β (TGF-β) cascade and inflammatory responses in vivo. Additionally, the effects of SCE upon the collagen production, TGF-β/Smad3 (SMAD family member 3) signaling, and the levels of histone methylation in primary cardiac fibroblasts were detected. We found that SCE treatment significantly improved survival and left ventricular function in mice after MI. Inhibition of inflammation and fibrosis, as well as decreased expression of Smad3, was observed with SCE treatment. In TGF-β-stimulated cardiac fibroblasts, SCE significantly decreased the expression of collagen, α-smooth muscle actin (α-SMA), and Smad3. Furthermore, SCE treatment downregulated the levels of H3K4 trimethylation (H3K4me3) and H3K36 trimethylation (H3K36me3) at the Smad3 promoter region of cardiac fibroblasts, leading to inhibition of Smad3 transcription. Our findings suggested that SCE prevents myocardial fibrosis and adverse remodeling after MI with a novel mechanism of suppressing histone methylation of the Smad3 promoter and its transcription.