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 |