C-reactive protein-mediated vascular injury requires complement.

Area of Science:

• Cardiovascular Biology
• Immunology
• Vascular Medicine

Background:

• Vascular injury triggers neointima formation, a process exaggerated in human C-reactive protein (CRP) transgenic (CRPtg) mice compared to nontransgenic (NTG) controls.
• The role of the complement system in CRP-mediated neointima formation remains to be elucidated.

Purpose of the Study:

• To investigate whether the complement system is required for the exaggerated neointima formation observed in CRPtg mice following vascular injury.
• To determine the specific role of complement component 3 (C3) in this process.

Main Methods:

• Comparison of neointima formation in CRPtg and NTG mice with normal complement versus those lacking C3 (CRPtg/C3(-/-) and NTG/C3(-/-)) after carotid artery ligation.
• Assessment of C3 levels in serum and injured vessels.
• Administration of an antisense oligonucleotide to reduce human CRP levels.
• In vitro studies using bone marrow-derived macrophages to assess C3 expression.

Main Results:

• CRPtg mice exhibited significantly thicker neointimas and increased C3 deposition in injured carotid arteries compared to NTG mice.
• Neointima formation was not increased in CRPtg/C3(-/-) mice, indicating C3 dependence.
• Reducing human CRP levels diminished C3 depletion and deposition in injured vessels.
• In vitro, human CRP stimulated C3 production by macrophages, and C3 colocalized with macrophages in injured vessels.

Conclusions:

• Human CRP exacerbates neointima formation in injured arteries, a process dependent on complement component 3 (C3).
• Eliminating C3 or reducing CRP levels prevents CRP-driven exacerbation of the vascular injury response.
• Mouse C3 is essential for the exaggerated neointima formation mediated by human CRP in this model system.