The vital pathological processes in intimal hyperplasia include aberrant vascular smooth muscle cells (VSMCs) proliferation, migration, and phenotypic switching. Rosmarinic acid (RA) is a natural phenolic acid compound. Nevertheless, the underlying mechanism of RA in neointimal hyperplasia is still unclear. Our analysis illustrated that miR-25-3p mimics significantly enhanced PDGF-BB-mediated VSMCs proliferation, migration, and phenotypic switching while RA partially weakened the effect of miR-25-3p. Mechanistically, we found that miR-25-3p directly targets sirtuin (SIRT6). The suppressive effect of the miR-25-3p inhibitor on PDGF-BB-induced VSMCs proliferation, migration, and phenotypic switch was partially eliminated by SIRT6 knockdown. The suppression of the PDGF-BB-stimulated Nrf2/ARE signaling pathway that was activated by the miR-25-3p inhibitor was exacerbated by the SIRT6 knockdown. In in vivo experiments, RA reduced the degree of intimal hyperplasia while miR-25-3p agomir partially reversed the suppressive effect of RA in vascular remodeling. Our results indicate that RA activates the Nrf2/ARE signaling pathway via the miR-25-3p/SIRT6 axis to inhibit vascular remodeling.

中文翻译：

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迷迭香酸通过 miR-25-3p/SIRT6 轴激活 Nrf2/ARE 信号通路抑制血管重塑

内膜增生的重要病理过程包括异常血管平滑肌细胞（VSMC）增殖、迁移和表型转换。迷迭香酸（RA）是一种天然酚酸化合物。然而，RA引起内膜增生的潜在机制仍不清楚。我们的分析表明，miR-25-3p 模拟物显着增强 PDGF-BB 介导的 VSMC 增殖、迁移和表型转换，而 RA 部分削弱了 miR-25-3p 的作用。从机制上讲，我们发现 miR-25-3p 直接靶向 Sirtuin (SIRT6)。SIRT6 敲除部分消除了 miR-25-3p 抑制剂对 PDGF-BB 诱导的 VSMC 增殖、迁移和表型转换的抑制作用。SIRT6 敲低加剧了由 miR-25-3p 抑制剂激活的 PDGF-BB 刺激的 Nrf2/ARE 信号通路的抑制。在体内实验中，RA降低了内膜增生程度，而miR-25-3p agomir部分逆转了RA对血管重塑的抑制作用。我们的结果表明，RA 通过 miR-25-3p/SIRT6 轴激活 Nrf2/ARE 信号通路，从而抑制血管重塑。