RRC ID 81269
Author Hashikawa-Hobara N, Inoue S, Hashikawa N.
Title Lack of alpha CGRP exacerbates the development of atherosclerosis in ApoE-knockout mice.
Journal Sci Rep
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.
Volume 14(1)
Pages 18377
Published 2024-8-8
DOI 10.1038/s41598-024-69331-5
PII 10.1038/s41598-024-69331-5
PMID 39112593
PMC PMC11306347
MeSH Animals Antibodies, Monoclonal, Humanized / pharmacology Aorta / drug effects Aorta / metabolism Aorta / pathology Apolipoproteins E* / deficiency Apolipoproteins E* / genetics Atherosclerosis* / genetics Atherosclerosis* / metabolism Atherosclerosis* / pathology Calcitonin Gene-Related Peptide* / metabolism Cell Movement / drug effects Diet, High-Fat / adverse effects Disease Models, Animal Etanercept / pharmacology Humans Male Mice Mice, Inbred C57BL Mice, Knockout* Mice, Knockout, ApoE Plaque, Atherosclerotic* / genetics Plaque, Atherosclerotic* / metabolism Plaque, Atherosclerotic* / pathology Tumor Necrosis Factor-alpha / metabolism
Resource
Mice RBRC04109