Homocysteine (Hcy) is considered an independent risk factor for various cardiovascular diseases including atherosclerosis which is associated with lipid metabolism, inflammation, and oxidative stress. Results from our previous study suggested that Hcy-induced atherosclerosis could be reversed by Herpud1 knockout which inhibits vascular smooth muscle cell (VSMC) phenotype switching. Here, we aim to investigate more precise mechanisms behind the improvement in Hcy-induced atherosclerosis. Amyloid-β40 (Aβ40), a vital protein in Alzheimer disease (AD), has been regarded as an important component in the atherosclerosis program in recent years due to the biological similarity between AD and atherosclerosis. Thus, we determined to assess the value of Aβ40 in a Herpud1 knockout Hcy-induced atherosclerosis mouse model by measuring Aβ40 expression in tissue and biomarkers of lipid metabolism, inflammation, and oxidative stress in serum. Additionally, since endothelial dysfunction plays a prominent role in atherosclerosis, we tested human umbilical vein endothelial cell (HUVEC) function following Herpud1 silencing in vitro and evaluated JNK/AP1 signaling activation in our models because of its close relationship with Aβ40. As a result, our animal models showed that Herpud1 knockout reduced Aβ40 expression, inflammation, and oxidative stress levels other than lipid metabolism and alleviated atherosclerosis via JNK/AP1 signaling inhibition. Similarly, our cell experiments implied that Hcy-induced Aβ40 elevation and HUVEC dysfunction involving cell proliferation and apoptosis could be restored by Herpud1 silence through restraining JNK/AP1 pathway. Collectively, our study demonstrates that Herpud1 deficiency could reduce Aβ40 expression, thereby suppressing Hcy-induced atherosclerosis by blocking the JNK/AP1 pathway. This may provide novel potential targets for atherosclerosis prevention or treatment.

中文翻译：

---

Herpud1缺乏症可通过阻断JNK / AP1途径来降低淀粉样蛋白β40的表达，从而抑制高半胱氨酸诱导的动脉粥样硬化。

同型半胱氨酸（Hcy）被认为是各种心血管疾病（包括与脂质代谢，炎症和氧化应激相关的动脉粥样硬化）的独立危险因素。我们先前研究的结果表明，Hypud1基因敲除可逆转Hcy诱导的动脉粥样硬化，后者可抑制血管平滑肌细胞（VSMC）表型转换。在这里，我们旨在研究Hcy诱导的动脉粥样硬化改善背后的更精确的机制。淀粉样蛋白-β40（Aβ40）是阿尔茨海默病（AD）的重要蛋白，由于AD与动脉粥样硬化之间的生物学相似性，近年来已被认为是动脉粥样硬化计划的重要组成部分。从而，我们决定通过测量组织中的Aβ40表达以及血清脂质代谢，炎症和氧化应激的生物标志物来评估在Herpud1基因敲除的Hcy诱导的动脉粥样硬化小鼠模型中Aβ40的价值。此外，由于内皮功能障碍在动脉粥样硬化中起着重要作用，因此我们在体外Herpud1沉默后测试了人脐静脉内皮细胞（HUVEC）的功能，并在模型中评估了JNK / AP1信号激活，因为它与Aβ40密切相关。结果，我们的动物模型显示，除脂质代谢外，Herpud1基因敲除降低了Aβ40表达，炎症和氧化应激水平，并通过JNK / AP1信号传导抑制减轻了动脉粥样硬化。同样，我们的细胞实验表明，通过抑制JNK / AP1途径，Herpud1沉默可以恢复Hcy诱导的Aβ40升高和涉及细胞增殖和凋亡的HUVEC功能障碍。总体而言，我们的研究表明，Herpud1缺乏症可以降低Aβ40表达，从而通过阻断JNK / AP1途径抑制Hcy诱导的动脉粥样硬化。这可以为预防或治疗动脉粥样硬化提供新的潜在靶标。