<br>丹参醇通过靶向 ERK2 和干扰 ERK2Thr188 的分子间自磷酸化来缓解缺血诱导的心肌纤维化,Biomedicine & Pharmacotherapy

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丹参醇通过靶向 ERK2 和干扰 ERK2Thr188 的分子间自磷酸化来缓解缺血诱导的心肌纤维化
Biomedicine & Pharmacotherapy ( IF 6.9 ) Pub Date : 2023-10-18 , DOI: 10.1016/j.biopha.2023.115729
Wei Lei ₁ , Chun-Yan Chen ₁ , Feng-Jie Zhou ₁ , Yao-Lei Ma ₁ , Yu-Hong Li ₁ , Han Zhang ₁

Affiliation

心肌纤维化是心肌缺血（MI）的基本重塑过程，也是导致心力衰竭和死亡的主要原因。丹参素（中文丹参素，DSS）是唇形科丹参根的主要成分，具有显著的心脏保护作用。在这项研究中，我们旨在确定行动靶点，然后揭示 DSS 缓解心肌纤维化的机制。评估 DSS 保护缺血性心脏的药理活性，并进行心肌蛋白质组学研究。为了确定 DSS 的靶标，进行了细胞热转移测定结合 LC-MS 鉴定。采用表面等离子体共振测定、分子动力学模拟以及药理学和分子生物学方法来探索 DSS 的作用机制。我们的结果显示，DSS 有效缓解了 MI 诱导的左心室功能障碍和循环心肌标志物的增加。此外，DSS 显着逆转了与心肌纤维化过程相关的蛋白质组学特征，ERK2 被确定为 DSS 的关键细胞靶点。DSS 以剂量依赖性方式减轻 ERK2 的温度依赖性变性，DSS 和 ERK2 的 KD 值为 60.19 μM。Ang II 刺激后，DSS 抑制了 Thr188 的磷酸化，而不是 TEY 基序中的经典残基。DSS 干扰 ERK2 同源二聚化，然后阻断 Thr188 位点的分子间自磷酸化。因此，DSS 抑制了 ERK2 的核转位和下游纤维化生物分子的表达。总的来说，我们的结果表明 DSS 靶向 ERK2 并抑制 Thr188 残基的分子间自磷酸化，从而保护缺血性心肌免受纤维化重塑。

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Tanshinol alleviates ischemia-induced myocardial fibrosis via targeting ERK2 and disturbing the intermolecular autophosphorylation of ERK2Thr188

Myocardial fibrosis is the fundamental remodeling process in myocardial ischemia (MI) and also the major contributor of heart failure and death. Tanshinol (Danshensu in Chinese, DSS), a major ingredient of salvia mitiorrhiza Bunge (Lamiaceae) root, exerted significant cardio protection effects. In this study, we aimed to identify the action target and then uncover the mechanism of DSS alleviating myocardial fibrosis. The pharmacological activities of DSS protecting ischemic cardiac was assessed and the myocardial proteomics was carried out. To identify the target of DSS, a cellular thermal shift assay combined with LC-MS identification was conducted. Surface plasmon resonance assay, molecular dynamics simulation and pharmacological and molecular biology approaches were adopted to explore the action mechanisms of DSS. Our results revealed that DSS effectively alleviated MI-induced left ventricle dysfunctions and the increasements of circulating myocardial markers. Besides, DSS significantly reversed the proteomic profile related to myocardial fibrotic processes and the ERK2 was identified as a crucial cellular target of DSS. DSS abated the temperature-dependent denaturation of ERK2 in a dose-dependent manner and the KD value of DSS and ERK2 was 60.19 μM. After Ang II stimulation, DSS suppressed the phosphorylation of Thr188 rather than the classic residues in TEY motif. DSS interfered the ERK2 homo-dimerization and then blocked the intermolecular autophosphorylation at Thr188 site. Thereout, DSS inhibited the nuclear translocation of ERK2 and the expression of downstream fibrotic biomolecules. Collectively, our results demonstrated that DSS targeted ERK2 and suppressed the intermolecular autophosphorylation at Thr188 residue, thus protecting ischemic myocardia from fibrosis remodeling.

更新日期：2023-10-18

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