Objective: Post myocardial infarction (MI) fibrosis has been identified as an important factor in the progression of heart failure. Previous studies have revealed that microRNA-21 (miR-21) plays an important role in the pathogenesis of fibrosis. The purpose of this study was to explore the role of miR-21 in post-MI cardiac fibrosis.
Material and Methods: MI was established in wild-type (WT) and miR-21 knockout (KO) mice. Primary mice cardiac fibroblasts (CFs) were isolated from WT and miR-21 KO mice and were treated with angiotensin II (Ang II) or Sprouty1 (Spry1) siRNA. Histological analysis and echocardiography were used to determine the extent of fibrosis and cardiac function.
Results: Compared with WT mice, miR-21 KO mice displayed smaller fibrotic areas and decreased expression of fibrotic markers and inflammatory cytokines. In parallel, Ang II-induced myofibroblasts transformation was partially inhibited upon miR-21 KO in primary CFs. Mechanistically, we found that the expression of Spry1, a previously reported target of miR-21, was markedly increased in miR-21 KO mice post MI, further inhibiting ERK1/2 activation. In vitro studies showed that Ang II activated ERK1/2/TGF-β/Smad2/3 pathway. Phosphorylated Smad2/3 further enhanced the expression of α-SMA and FAP and may promote the maturation of miR-21, thereby downregulating Spry1. Additionally, these effects of miR-21 KO on fibrosis were reversed by siRNA-mediated knockdown of Spry1.
Conclusion: Our findings suggest that miR-21 promotes post-MI fibrosis by targeting Spry1. Furthermore, it mediates a positive feedback on Ang II, thereby inducing the ERK/TGF-β/Smad pathway. Therefore, targeting the miR-21–Spry1 axis may be a promising therapeutic option for ameliorating post-MI cardiac fibrosis.

Keywords: cardiac fibrosis, myocardial infarction, microRNA-21, Sprouty1, ERK/TGF-β/Smad signaling pathway


中文翻译：

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MicroRNA-21 介导对血管紧张素 II 诱导的肌成纤维细胞转化的积极反馈

目的：心肌梗死后（MI）纤维化已被确定为心力衰竭进展的重要因素。以往的研究表明，microRNA-21（miR-21）在纤维化的发病机制中起重要作用。本研究的目的是探讨 miR-21 在 MI 后心脏纤维化中的作用。
材料和方法：在野生型 (WT) 和 miR-21 敲除 (KO) 小鼠中建立 MI。从 WT 和 miR-21 KO 小鼠中分离出原代小鼠心脏成纤维细胞 (CF)，并用血管紧张素 II (Ang II) 或 Sprouty1 (Spry1) siRNA 处理。组织学分析和超声心动图用于确定纤维化程度和心脏功能。
结果：与 WT 小鼠相比，miR-21 KO 小鼠的纤维化区域更小，纤维化标志物和炎性细胞因子的表达降低。同时，Ang II 诱导的肌成纤维细胞转化在原发性 CF 中被 miR-21 KO 部分抑制。从机制上讲，我们发现先前报道的 miR-21 靶标 Spry1 的表达在 MI 后的 miR-21 KO 小鼠中显着增加，进一步抑制了 ERK1/2 的激活。体外研究表明，Ang II 激活了 ERK1/2/TGF-β/Smad2/3 通路。磷酸化的 Smad2/3 进一步增强了 α-SMA 和 FAP 的表达，并可能促进 miR-21 的成熟，从而下调 Spry1。此外，miR-21 KO 对纤维化的这些影响被 siRNA 介导的 Spry1 敲低逆转。
结论：我们的研究结果表明，miR-21 通过靶向 Spry1 促进 MI 后纤维化。此外，它介导对 Ang II 的正反馈，从而诱导 ERK/TGF-β/Smad 通路。因此，靶向 miR-21-Spry1 轴可能是改善 MI 后心脏纤维化的有希望的治疗选择。

关键词：心脏纤维化，心肌梗死，microRNA-21，Sprouty1，ERK/TGF-β/Smad信号通路