Zhu Baoling, Yang Yi, Wang Xiangfei, Sun Dili, Yang Xiyang, Zhu Xiaowei, Ding Suling, Xiao Chun, Zou Yunzeng, Yang Xiangdong
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital & Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Shandong, 266071, China.
J Mol Med (Berl). 2024 Jul;102(7):887-897. doi: 10.1007/s00109-024-02453-5. Epub 2024 May 11.
Atherosclerosis (AS) is a chronic inflammatory arterial disease, in which abnormal lipid metabolism and foam cell formation play key roles. Histamine is a vital biogenic amine catalyzed by histidine decarboxylase (HDC) from L-histidine. Histamine H1 receptor (HR) antagonist is a commonly encountered anti-allergic agent in the clinic. However, the role and mechanism of HR in atherosclerosis have not been fully elucidated. Here, we explored the effect of HR on atherosclerosis using Apolipoprotein E-knockout (ApoE) mice with astemizole (AST, a long-acting HR antagonist) treatment. The results showed that AST increased atherosclerotic plaque area and hepatic lipid accumulation in mice. The result of microarray study identified a significant change of endothelial lipase (LIPG) in CD11b myeloid cells derived from HDC-knockout (HDC) mice compared to WT mice. Blocking HR promoted the formation of foam cells from bone marrow-derived macrophages (BMDMs) of mice by up-regulating p38 mitogen-activated protein kinase (p38 MAPK) and LIPG signaling pathway. Taken together, these findings demonstrate that blocking HR signal aggravates atherosclerosis by promoting abnormal lipid metabolism and macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway. KEY MESSAGES: Blocking HR signal with AST aggravated atherosclerosis and increased hepatic lipid accumulation in high-fat diet (HFD)-fed ApoE mice. Blocking HR signal promoted macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway.
动脉粥样硬化（AS）是一种慢性炎症性动脉疾病，其中异常脂质代谢和泡沫细胞形成起着关键作用。组胺是一种由组氨酸脱羧酶（HDC）催化L-组氨酸产生的重要生物胺。组胺H1受体（HR）拮抗剂是临床上常用的抗过敏药物。然而，HR在动脉粥样硬化中的作用和机制尚未完全阐明。在此，我们使用阿苯达唑（AST，一种长效HR拮抗剂）处理载脂蛋白E基因敲除（ApoE）小鼠，探讨HR对动脉粥样硬化的影响。结果表明，AST增加了小鼠的动脉粥样硬化斑块面积和肝脏脂质积累。微阵列研究结果显示，与野生型小鼠相比，来自HDC基因敲除（HDC）小鼠的CD11b髓样细胞中内皮脂肪酶（LIPG）有显著变化。阻断HR通过上调p38丝裂原活化蛋白激酶（p38 MAPK）和LIPG信号通路促进小鼠骨髓来源巨噬细胞（BMDM）形成泡沫细胞。综上所述，这些发现表明，阻断HR信号通过p38 MAPK-LIPG信号通路促进异常脂质代谢和巨噬细胞衍生的泡沫细胞形成，从而加重动脉粥样硬化。关键信息：用AST阻断HR信号会加重高脂饮食（HFD）喂养的ApoE小鼠的动脉粥样硬化并增加肝脏脂质积累。阻断HR信号通过p38 MAPK-LIPG信号通路促进巨噬细胞衍生的泡沫细胞形成。
