Restenosis after angioplasty of peripheral arteries is a clinical problem involving oxidative stress. Hydrogen sulfide (H₂S) participates in oxidative stress regulation and activates nuclear factor erythroid 2-related factor 2 (Nrf2). This study investigated the effect of H₂S and Nrf2 on restenosis-induced arterial injury. Using an in vivo rat model of restenosis, we investigated whether H₂S inhibits restenosis after percutaneous transluminal angioplasty (PTA) and the oxidative stress-related mechanisms implicated therein. The involvement of Nrf2 was explored using Nrf2-shRNA. Neointimal formation and the deposition of elastic fibers were assessed histologically. Inflammatory cytokine secretion and the expression of proteins associated with oxidative stress and inflammation were evaluated. The artery of rats subjected to restenosis showed increased arterial intimal thickness, with prominent elastic fiber deposition. Sodium hydrosulfide (NaHS), an H₂S donor, counteracted these changes in vivo. Restenosis caused a decrease in anti-oxidative stress signaling. This phenomenon was inhibited by NaHS, but Nrf2-shRNA counteracted the effects of NaHS. In terms of inflammation, inflammatory cytokines were upregulated, whereas NaHS suppressed the induced inflammatory reaction. Similarly, Nrf2 downregulation blocked the effect of NaHS. In vitro studies using aortic endothelial and vascular smooth muscle cells isolated from experimental animals showed consistent results as those of in vivo studies, and the participation of the nuclear factor-kappa B signaling pathway was demonstrated. Collectively, H₂S played a role in regulating post-PTA restenosis by alleviating oxidative stress, modulating anti-oxidant defense, and targeting Nrf2-related pathways via nuclear factor-kappa B signaling.

Impact statement

This work advances the field of vascular pharmacology as it addresses the issue of neointimal hyperplasia, which is a severe problem that results in restenosis after percutaneous transluminal angioplastic surgery. The effectiveness of vascular surgery is impacted negatively because of this phenomenon, and a solution is urgently needed. Here, we report in a rat model of angioplasty-induced vessel injury that hydrogen sulfide (H₂S) counteracts post-percutaneous transluminal angioplasty neointimal formation and inflammation. Importantly, we demonstrated that the action of H₂S requires Nrf2 signaling and is associated with the regulation of oxidative stress and inflammation via the nuclear factor-kappa B signaling pathway. Notably, our findings offer a potential strategy to address post-vascular surgery restenosis, which remains a clinical problem.

中文翻译：

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H2S 通过 Nrf2/NF-κB 信号减弱氧化应激，调节经皮腔内血管成形术后的再狭窄

外周动脉血管成形术后的再狭窄是涉及氧化应激的临床问题。硫化氢 (H ₂ S) 参与氧化应激调节并激活核因子红细胞 2 相关因子 2 (Nrf2)。本研究调查了 H ₂ S 和 Nrf2 对再狭窄引起的动脉损伤的影响。使用再狭窄的体内大鼠模型，我们研究了H ₂ S是否抑制经皮腔内血管成形术（PTA）后的再狭窄以及其中涉及的氧化应激相关机制。使用 Nrf2-shRNA 探索了 Nrf2 的参与。通过组织学评估新内膜形成和弹性纤维的沉积。评估了炎症细胞因子的分泌以及与氧化应激和炎症相关的蛋白质的表达。再狭窄大鼠动脉显示动脉内膜厚度增加，弹力纤维沉积明显。氢硫化钠 (NaHS)，一种 H ₂ S 供体，在体内抵消了这些变化。再狭窄导致抗氧化应激信号减少。这种现象被 NaHS 抑制，但 Nrf2-shRNA 抵消了 NaHS 的影响。在炎症方面，炎症细胞因子上调，而NaHS抑制诱导的炎症反应。同样，Nrf2 下调阻断了 NaHS 的作用。使用从实验动物中分离的主动脉内皮和血管平滑肌细胞进行的体外研究显示出与体内研究一致的结果，并且证明了核因子-κB信号通路的参与。 总的来说，H ₂ S 通过减轻氧化应激、调节抗氧化防御以及通过核因子-kappa B 信号传导靶向 Nrf2 相关途径，在调节 PTA 后再狭窄中发挥作用。

 影响报告

这项工作推动了血管药理学领域的发展，因为它解决了新内膜增生的问题，这是导致经皮腔内血管成形手术后再狭窄的严重问题。由于这种现象，血管手术的有效性受到负面影响，迫切需要一种解决方案。在这里，我们在血管成形术引起的血管损伤的大鼠模型中报告，硫化氢（H ₂ S）可以抵消经皮腔内血管成形术后的新内膜形成和炎症。重要的是，我们证明H ₂ S的作用需要Nrf2信号传导，并且通过核因子-κB信号通路与氧化应激和炎症的调节相关。值得注意的是，我们的研究结果提供了解决血管手术后再狭窄的潜在策略，这仍然是一个临床问题。