Lack of alpha CGRP exacerbates the development of atherosclerosis in ApoE-knockout mice

Sci Rep. 2024 Aug 8;14(1):18377. doi: 10.1038/s41598-024-69331-5.

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.

MeSH terms

  • 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

Substances

  • Calcitonin Gene-Related Peptide
  • Apolipoproteins E
  • Tumor Necrosis Factor-alpha
  • Antibodies, Monoclonal, Humanized
  • Etanercept