Key Laboratory of Ministry of Education for Medical Electrophysiology and the Institute of Cardiovascular Research, Southwest Medical University, 319 Zhongshan Road, Luzhou, Sichuan 646000, China.
Drug Discovery Research Center, Southwest Medical University, 319 Zhongshan Road, Luzhou, Sichuan 646000, China.
Oxid Med Cell Longev. 2018 Jul 24;2018:6712585. doi: 10.1155/2018/6712585. eCollection 2018.
Differentiation of atrial fibroblasts into myofibroblasts plays a critical role in atrial fibrosis. Sodium tanshinone IIA sulfonate (DS-201), a water-soluble derivative of tanshinone IIA, has been shown to have potent antifibrotic properties. However, the protective effects of DS-201 on angiotensin II- (Ang II-) induced differentiation of atrial fibroblasts into myofibroblasts remain to be elucidated. In this study, human atrial fibroblasts were stimulated with Ang II in the presence or absence of DS-201. Then, -smooth muscle actin (-SMA), collagen I, and collagen III expression and reactive oxygen species (ROS) generation were measured. The expression of transforming growth factor-1 (TGF-1) and the downstream signaling of TGF-1, such as phosphorylation of Smad2/3, were also determined. The results demonstrated that DS-201 significantly prevented Ang II-induced human atrial fibroblast migration and decreased Ang II-induced -SMA, collagen I, and collagen III expression. Furthermore, increased production of ROS and expression of TGF-1 stimulated by Ang II were also significantly inhibited by DS-201. Consistent with these results, DS-201 significantly inhibited Ang II-evoked Smad2/3 phosphorylation and periostin expression. These results and the experiments involving N-acetyl cysteine (antioxidant) and an anti-TGF-1 antibody suggest that DS-201 prevent Ang II-induced differentiation of atrial fibroblasts to myofibroblasts, at least in part, through suppressing oxidative stress and inhibiting the activation of TGF-1 signaling pathway. All of these data indicate the potential utility of DS-201 for the treatment of cardiac fibrosis.
心房成纤维细胞向肌成纤维细胞的分化在心房纤维化中起着关键作用。丹参酮 IIA 磺酸钠（DS-201）是丹参酮 IIA 的水溶性衍生物，已被证明具有很强的抗纤维化特性。然而，DS-201 对血管紧张素 II（Ang II）诱导的心房成纤维细胞向肌成纤维细胞分化的保护作用仍有待阐明。在这项研究中，用 Ang II 刺激人源性心房成纤维细胞，同时存在或不存在 DS-201。然后，测量 -平滑肌肌动蛋白（-SMA）、胶原 I 和胶原 III 的表达和活性氧（ROS）的产生。还测定了转化生长因子-1（TGF-1）的表达及其下游信号，如 Smad2/3 的磷酸化。结果表明，DS-201 显著抑制 Ang II 诱导的人源性心房成纤维细胞迁移，并降低 Ang II 诱导的 -SMA、胶原 I 和胶原 III 的表达。此外，由 Ang II 刺激产生的 ROS 增加和 TGF-1 的表达也被 DS-201 显著抑制。与这些结果一致的是，DS-201 显著抑制 Ang II 诱导的 Smad2/3 磷酸化和periostin表达。这些结果以及涉及 N-乙酰半胱氨酸（抗氧化剂）和抗 TGF-1 抗体的实验表明，DS-201 通过抑制氧化应激和抑制 TGF-1 信号通路的激活，至少部分地预防 Ang II 诱导的心房成纤维细胞向肌成纤维细胞的分化。所有这些数据表明，DS-201 有可能用于治疗心脏纤维化。
