Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany.
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Cardiovasc Res. 2022 Jan 7;118(1):156-168. doi: 10.1093/cvr/cvab041.
Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall and anti-inflammatory treatment strategies are currently pursued to lower cardiovascular disease burden. Modulation of recently discovered inactive rhomboid protein 2 (iRhom2) attenuates shedding of tumour necrosis factor-alpha (TNF-α) selectively from immune cells. The present study aims at investigating the impact of iRhom2 deficiency on the development of atherosclerosis.
Low-density lipoprotein receptor (LDLR)-deficient mice with additional deficiency of iRhom2 (LDLR-/-iRhom2-/-) and control (LDLR-/-) mice were fed a Western-type diet (WD) for 8 or 20 weeks to induce early or advanced atherosclerosis. Deficiency of iRhom2 resulted in a significant decrease in the size of early atherosclerotic plaques as determined in aortic root cross-sections. LDLR-/-iRhom2-/- mice exhibited significantly lower serum levels of TNF-α and lower circulating and hepatic levels of cholesterol and triglycerides compared to LDLR-/- mice at 8 weeks of WD. Analyses of hepatic bile acid concentration and gene expression at 8 weeks of WD revealed that iRhom2 deficiency prevented WD-induced repression of hepatic bile acid synthesis in LDLR-/- mice. In contrast, at 20 weeks of WD, plaque size, plaque composition, and serum levels of TNF-α or cholesterol were not different between genotypes.
Modulation of inflammation by iRhom2 deficiency attenuated diet-induced hyperlipidaemia and early atherogenesis in LDLR-/- mice. iRhom2 deficiency did not affect diet-induced plaque burden and composition in advanced atherosclerosis in LDLR-/- mice.
动脉粥样硬化是动脉血管壁的一种慢性炎症性疾病，目前正在寻求抗炎治疗策略来降低心血管疾病负担。最近发现的无活性菱形蛋白 2（iRhom2）的调节作用可选择性地从免疫细胞中减轻肿瘤坏死因子-α（TNF-α）的脱落。本研究旨在探讨 iRhom2 缺乏对动脉粥样硬化发展的影响。
载脂蛋白 B100 基因敲除（apoE-/-）小鼠和载脂蛋白 E 基因敲除（apoE-/-）小鼠分别补充缺乏 iRhom2（apoE-/-iRhom2-/-）和对照（apoE-/-）小鼠，喂食西方饮食（WD）8 或 20 周，以诱导早期或晚期动脉粥样硬化。iRhom2 缺乏导致主动脉根部横切片中早期动脉粥样硬化斑块的大小显著减小。与 apoE-/- 小鼠相比，apoE-/-iRhom2-/- 小鼠在 WD 8 周时血清 TNF-α水平和循环及肝胆固醇和甘油三酯水平显著降低。WD 8 周时肝胆汁酸浓度和基因表达分析显示，iRhom2 缺乏可防止 WD 诱导的 apoE-/- 小鼠肝胆汁酸合成受抑制。相比之下，在 WD 20 周时，斑块大小、斑块组成、血清 TNF-α或胆固醇水平在两种基因型之间没有差异。
iRhom2 缺乏调节炎症反应可减轻 LDLR-/- 小鼠饮食诱导的高脂血症和早期动脉粥样硬化形成。在 LDLR-/- 小鼠晚期动脉粥样硬化中，iRhom2 缺乏不影响饮食诱导的斑块负担和组成。
