Introduction

Antioxidants represented by kaempferol have been shown to be effective against atherosclerosis (AS). However, the underlying mechanisms still remain unclear.

Objectives

The aim of this research was to reveal the mechanism of kaempferol regarding the treatment of AS and accumulation of foam cell.

Methods

We explored the contribution of kaempferol to the levels of inflammatory factors, scavenger receptor CD36, mitochondrial membrane potential, ROS, MAPK/NF-κB, Nrf2/HO-1, Ca²⁺ and Piezo1 levels in RAW264.7 macrophages exposed to ox-LDL. In addition, to explore whether kaempferol inhibits ox-LDL-induced foamy macrophage through Piezo1, we extracted macrophages from Piezo1 macrophage-specific knockout (Piezo1^ΔLysM) mice. For further validation, ApoE^-/- and Piezo1 macrophage-specific knockout mice (Piezo1^ΔLysM/ ApoE^-/-) were generated.

Results

The results showed that kaempferol notably suppressed inflammatory response, CD36 expression, mitochondrial membrane potential elevation, ROS production, MAPK/NF-κB expression, Ca²⁺ expression, and increased Nrf2/HO-1 levels in RAW264.7. In addition, depletion of macrophage Piezo1 also effectively reduced lipid droplet deposition, inflammatory factor expression, oxidative damage, MAPK/NF-κB, Ca²⁺ expression, and increased Nrf2/HO-1 expression in mouse BMDMs, and the results were still consistent after kaempferol treatment. In vivo studies have shown that kaempferol significantly reduces atherosclerotic plaque formation. However, the beneficial effect of kaempferol was attenuated in Piezo1 depletion mice.

Conclusions

These results collectively provide compelling evidence that kaempferol regulates CD36-mediated mitochondrial ROS production by inhibiting the Piezo1 channels and Ca²⁺ influx, and then regulates the downstream pathways of NF-κB/MAPK and HO-1/Nrf2, inhibiting to the formation of foam cells. In conclusion, this study revealed a potential mechanism by which the natural antioxidant kaempferol prevents foamy macrophage.

中文翻译：

---

山奈酚通过压电 1 介导的 MAPK/NF-κB 和 Nrf2/HO-1 信号通路调节巨噬细胞泡沫和动脉粥样硬化

 介绍

以山奈酚为代表的抗氧化剂已被证明对动脉粥样硬化 （AS） 有效。然而，其潜在机制仍不清楚。

 目标

本研究的目的是揭示山奈酚治疗 AS 和泡沫细胞积累的机制。

 方法

我们探讨了山奈酚对暴露于 ox-LDL 的 RAW26.7 巨噬细胞中炎症因子、清道夫受体 CD36、线粒体膜电位、ROS、MAPK/NF-κB、Nrf2/HO-1、Ca²⁺ 和 Piezo1 水平的贡献。此外，为了探讨山奈酚是否通过 Piezo1 抑制 ox-LDL 诱导的泡沫状巨噬细胞，我们从 Piezo1 巨噬细胞特异性敲除 （Piezo1^ΔLysM） 小鼠中提取了巨噬细胞。为了进一步验证，生成了 ApoE^-/- 和 Piezo1 巨噬细胞特异性敲除小鼠 （Piezo1^ΔLysM/ ApoE^-/-）。

 结果

结果显示，山奈酚显著抑制炎症反应、 CD36 表达、线粒体膜电位升高、 ROS 产生、MAPK/NF-κB 表达、Ca²⁺ 表达和 RAW264.7 中 Nrf2/HO-1 水平升高。此外，巨噬细胞 Piezo1 的耗竭还有效降低了小鼠 BMDMs 中脂滴沉积、炎症因子表达、氧化损伤、MAPK/NF-κB、Ca²⁺ 表达，并增加了 Nrf2/HO-1 的表达，山奈酚处理后结果仍然一致。体内研究表明，山奈酚可显着减少动脉粥样硬化斑块的形成。然而，山奈酚的有益作用在 Piezo1 耗竭小鼠中减弱。

 结论

这些结果共同提供了令人信服的证据，表明山奈酚通过抑制 Piezo1 通道和 Ca²⁺ 内流来调节 CD36 介导的线粒体 ROS 产生，然后调节 NF-κB/MAPK 和 HO-1/Nrf2 的下游途径，抑制泡沫细胞的形成。总之，这项研究揭示了天然抗氧化剂山奈酚防止泡沫状巨噬细胞的潜在机制。