Background

Macrophage-derived foam cells are a hallmark of atherosclerosis. Scavenger receptors, including lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (OLR-1), are the principal receptors responsible for the uptake and modification of LDL, facilitating macrophage lipid load and the uptake of oxidized LDL by arterial wall cells. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates the expression of genes by binding to the promoter during transcription. Therefore, this study aimed to investigate the precise role of macrophage KLF15 in atherogenesis.

Methods

We used two murine models of atherosclerosis: mice injected with an adeno-associated virus (AAV) encoding the Asp374-to-Tyr mutant version of human PCSK9, followed by 12 weeks on a high-fat diet (HFD), and ApoE^−/−‐ mice on a HFD. We subsequently injected mice with AAV-KLF15 and AAV-LacZ to assess the role of KLF15 in the development of atherosclerosis in vivo. Oil Red O, H&E, and Masson's trichome staining were used to evaluate atherosclerotic lesions. Western blots and RT-qPCR were used to assess protein and mRNA levels, respectively.

Results

We determined that KLF15 expression was downregulated during atherosclerosis formation, and KLF15 overexpression prevented atherosclerosis progression. KLF15 expression levels did not affect body weight or serum lipid levels in mice. However, KLF15 overexpression in macrophages prevented foam cell formation by reducing OLR-1-meditated lipid uptake. KLF15 directly targeted and transcriptionally downregulated OLR-1 levels. Restoration of OLR-1 reversed the beneficial effects of KLF15 in atherosclerosis.

Conclusion

Macrophage KLF15 transcriptionally downregulated OLR-1 expression to reduce lipid uptake, thereby preventing foam cell formation and atherosclerosis. Thus, our results suggest that KLF15 is a potential therapeutic target for atherosclerosis.

中文翻译：

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巨噬细胞 KLF15 通过 OLR-1 转录抑制来防止泡沫细胞形成和动脉粥样硬化

背景

巨噬细胞衍生的泡沫细胞是动脉粥样硬化的标志。清道夫受体，包括凝集素样氧化低密度脂蛋白（LDL）受体-1（OLR-1），是负责摄取和修饰LDL的主要受体，促进巨噬细胞脂质负荷和动脉壁对氧化LDL的摄取细胞。Krüppel 样因子 15 (KLF15) 是一种转录因子，在转录过程中通过与启动子结合来调节基因的表达。因此，本研究旨在探讨巨噬细胞KLF15在动脉粥样硬化形成中的确切作用。

方法

我们使用了两种动脉粥样硬化小鼠模型：给小鼠注射编码人 PCSK9 的 Asp374-to-Tyr 突变版本的腺相关病毒 (AAV)，然后进行 12 周的高脂肪饮食 (HFD) 和 ApoE - ^{/ −‐}使用 HFD 的小鼠。随后，我们给小鼠注射了 AAV- KLF15和 AAV- LacZ ，以评估 KLF15 在体内动脉粥样硬化发展中的作用。油红O、H&E和马森毛状体染色用于评估动脉粥样硬化病变。Western blots 和 RT-qPCR 分别用于评估蛋白质和 mRNA 水平。

结果

我们确定 KLF15 表达在动脉粥样硬化形成过程中下调，而 KLF15 过表达可阻止动脉粥样硬化进展。KLF15表达水平不影响小鼠的体重或血脂水平。然而，KLF15 在巨噬细胞中的过度表达通过减少 OLR-1 介导的脂质摄取来阻止泡沫细胞的形成。KLF15 直接靶向并转录下调 OLR-1 水平。OLR-1 的恢复逆转了 KLF15 在动脉粥样硬化中的有益作用。

结论

巨噬细胞KLF15转录下调OLR-1表达以减少脂质摄取，从而防止泡沫细胞形成和动脉粥样硬化。因此，我们的结果表明 KLF15 是动脉粥样硬化的潜在治疗靶点。