Macrophage polarization in response to environmental cues has emerged as an important event in the development of atherosclerosis. Compelling evidences suggest that P21-activated kinases 1 (PAK1) is involved in a wide variety of diseases. However, the potential role and mechanism of PAK1 in regulation of macrophage polarization remains to be elucidated. Here, we observed that PAK1 showed a dramatically increased expression in M1 macrophages but decreased expression in M2 macrophages by using a well-established in vitro model to study heterogeneity of macrophage polarization. Adenovirus-mediated loss-of-function approach demonstrated that PAK1 silencing induced an M2 macrophage phenotype-associated gene profiles but repressed the phenotypic markers related to M1 macrophage polarization. Additionally, dramatically decreased foam cell formation was found in PAK1 silencing-induced M2 macrophage activation which was accompanied with alternation of marker account for cholesterol efflux or influx from macrophage foam cells. Moderate results in lipid metabolism and foam cell formation were found in M1 macrophage activation mediated by AdshPAK1. Importantly, we presented mechanistic evidence that PAK1 knockdown promoted the expression of PPARγ, and the effect of macrophage activation regulated by PAK1 silencing was largely reversed when a PPARγ antagonist was utilized. Collectively, these findings reveal that PAK1 is an independent effector of macrophage polarization at least partially attributed to regulation of PPARγ expression, which suggested PAK1-PPARγ axis as a novel therapeutic strategy in atherosclerosis management.

中文翻译：

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PAK1 沉默通过增加 PPARγ 表达减弱促炎性巨噬细胞活化和泡沫细胞形成

响应环境线索的巨噬细胞极化已成为动脉粥样硬化发展中的一个重要事件。令人信服的证据表明 P21 激活激酶 1 (PAK1) 与多种疾病有关。然而，PAK1在调节巨噬细胞极化中的潜在作用和机制仍有待阐明。在这里，我们通过使用完善的体外模型研究巨噬细胞极化的异质性，观察到 PAK1 在 M1 巨噬细胞中的表达显着增加，但在 M2 巨噬细胞中的表达降低。腺病毒介导的功能丧失方法证明 PAK1 沉默诱导了 M2 巨噬细胞表型相关基因谱，但抑制了与 M1 巨噬细胞极化相关的表型标记。此外，在 PAK1 沉默诱导的 M2 巨噬细胞活化中发现泡沫细胞形成显着减少，这伴随着胆固醇流出或巨噬细胞泡沫细胞流入的标志物的变化。在 AdshPAK1 介导的 M1 巨噬细胞活化中发现了脂质代谢和泡沫细胞形成的中等结果。重要的是，我们提出了 PAK1 敲低促进 PPAR γ表达的机制证据，并且当 PPAR γ被 PAK1 沉默调节的巨噬细胞活化作用在很大程度上被逆转使用了拮抗剂。总的来说，这些发现表明 PAK1 是巨噬细胞极化的独立效应物，至少部分归因于 PPAR γ表达的调节，这表明 PAK1-PPAR γ轴是动脉粥样硬化管理中的一种新的治疗策略。