PDF(Pubmed)
Abstract：
The effects of calcitonin gene-related peptide (CGRP) on atherosclerosis remain unclear. We used apolipoprotein E-deficient (ApoE-/-) mice to generate double-knockout ApoE-/-:CGRP-/- mice lacking alpha CGRP. ApoE-/-:CGRP-/- mice exhibited larger atherosclerotic plaque areas, peritoneal macrophages with enhanced migration functions, and elevated levels of the inflammatory cytokine tumor necrosis factor (TNF)-⍺. Thus, we also explored whether inhibiting TNF-⍺ could improve atherosclerosis in ApoE-/-:CGRP-/- mice by administering etanercept intraperitoneally once a week (5 mg/kg) alongside a high-fat diet for 2 weeks. This treatment led to significant reductions in aortic root lesion size, atherosclerotic plaque area and macrophage migration in ApoE-/-:CGRP-/- mice compared with mice treated with human IgG (5 mg/kg). We further examined whether results observed in ApoE-/-:CGRP-/- mice could similarly be obtained by administering a humanized monoclonal CGRP antibody, galcanezumab, to ApoE-/- mice. ApoE-/- mice were subcutaneously administered galcanezumab at an initial dose of 50 mg/kg, followed by a dose of 30 mg/kg in the second week. Galcanezumab administration did not affect systolic blood pressure, serum lipid levels, or macrophage migration but led to a significant increase in lipid deposition at the aortic root. These findings suggest that alpha CGRP plays a critical role in inhibiting the progression of atherosclerosis.
摘要：
降钙素基因相关肽（CGRP）对动脉粥样硬化的影响尚不清楚。我们使用载脂蛋白E缺陷（ApoE-/-）小鼠产生双敲除ApoE-/-：CGRP-/-缺乏αCGRP的小鼠。ApoE-/-：CGRP-/-小鼠表现出较大的动脉粥样硬化斑块面积，具有增强的迁移功能的腹膜巨噬细胞，和炎症细胞因子肿瘤坏死因子（TNF）的水平升高。因此，我们还探讨了在ApoE-/-:CGRP-/-小鼠中,通过每周一次(5mg/kg)腹膜内给予依那西普和高脂饮食2周,抑制TNF-α是否能改善动脉粥样硬化.这种治疗导致主动脉根部病变大小显著减少，ApoE-/-：CGRP-/-小鼠与用人IgG（5mg/kg）治疗的小鼠相比的动脉粥样硬化斑块面积和巨噬细胞迁移。我们进一步检查了在ApoE-/-：CGRP-/-小鼠中观察到的结果是否可以类似地通过施用人源化单克隆CGRP抗体获得，galcanezumab,给ApoE-/-老鼠。ApoE-/-小鼠以50mg/kg的初始剂量皮下施用galcanezumab，然后在第二周给予30mg/kg的剂量。Galcanezumab给药不影响收缩压，血脂水平，或巨噬细胞迁移，但导致主动脉根部脂质沉积显着增加。这些发现表明αCGRP在抑制动脉粥样硬化的进展中起关键作用。
