Mevastatin (MVS) is known for its anti‐inflammatory effects, potentially achieved by upregulating heme oxygenase‐1 (HO‐1), an enzyme involved in cytoprotection against oxidative injury. Nonetheless, the specific processes by which MVS stimulates HO‐1 expression in human cardiac fibroblasts (HCFs) are not yet fully understood. In this study, we found that MVS treatment increased HO‐1 mRNA and protein levels in HCFs. This induction was inhibited by pretreatment with specific inhibitors of p38 MAPK, JNK1/2, and FoxO1, and by siRNAs targeting NOX2, p47phox, p38, JNK1, FoxO1, Keap1, and Nrf2. MVS also triggered ROS generation and activated JNK1/2 and p38 MAPK, both attenuated by NADPH oxidase or ROS inhibitors. Additionally, MVS promoted the phosphorylation of FoxO1 and Nrf2, which was suppressed by p38 MAPK or JNK1/2 inhibitor. Furthermore, MVS inhibited TNF‐α‐induced NF‐κB activation and vascular cell adhesion molecule‐1 (VCAM‐1) expression via the HO‐1/CO pathway in HCFs. In summary, the induction of HO‐1 expression in HCFs by MVS is mediated through two primary signaling pathways: NADPH oxidase/ROS/p38 MAPK, and JNK1/2/FoxO1 and Nrf2. This research illuminates the underlying processes through which MVS exerts its anti‐inflammatory effects by modulating HO‐1 in cardiac fibroblasts.

中文翻译：

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美伐他汀诱导的心脏成纤维细胞中 HO-1 表达：对抗心血管炎症和纤维化的策略


美伐他汀 （MVS） 以其抗炎作用而闻名，可能是通过上调血红素加氧酶-1 （HO-1） 来实现的，HO-1 是一种参与细胞保护免受氧化损伤的酶。尽管如此，MVS 刺激人心脏成纤维细胞 （HCF） 中 HO-1 表达的具体过程尚不完全清楚。在这项研究中，我们发现 MVS 治疗增加了 HCF 中的 HO-1 mRNA 和蛋白质水平。用 p38 MAPK、JNK1/2 和 FoxO1 的特异性抑制剂以及靶向 NOX2、p47phox、p38、JNK1、FoxO1、Keap1 和 Nrf2 的 siRNA 预处理抑制了这种诱导。MVS 还触发了 ROS 的产生并激活了 JNK1/2 和 p38 MAPK，两者均被 NADPH 氧化酶或 ROS 抑制剂减弱。此外，MVS 促进 FoxO1 和 Nrf2 的磷酸化，而 FoxO1 和 Nrf2 的磷酸化被 p38 MAPK 或 JNK1/2 抑制剂抑制。此外，MVS 通过 HCF 中的 HO-1/CO 通路抑制 TNF α诱导的 NF-κB 活化和血管细胞粘附分子-1 （VCAM-1） 表达。总之，MVS 诱导 HCF 中 HO-1 的表达是通过两个主要信号通路介导的：NADPH 氧化酶/ROS/p38 MAPK 以及 JNK1/2/FoxO1 和 Nrf2。这项研究阐明了 MVS 通过调节心脏成纤维细胞中的 HO-1 发挥其抗炎作用的潜在过程。