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Complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice
Fan Zhang1, Kexin Yao1, Yan Liu1
1Beijing Anzhen Hospital, Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing Institute of Heart, Lung and Vascular Diseases, Capital Medical University, Ministry of Education, Beijing, 100029, China.
Abstract:
Mutations in fibrillin 1 (FBN1) is the main cause of Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. Activation of the complement system plays a key role in the formation of thoracic and abdominal aortic aneurysms. However, the role of the complement system in MFS-associated aortic aneurysms remains unclear. In this study, we observed increased levels of complement C3a and C5a in the plasma of MFS patients and mouse, and the increased deposition of the activated complement system product C3b/iC3b was also observed in the elastic fiber rupture zone of 3-month-old MFS mice. The expression of C3a receptor (C3aR) was increased in MFS aortas, and recombinant C3a promoted the expression of cytokines in macrophages. The administration of a C3aR antagonist (C3aRA) attenuated the development of thoracic aortic aneurysms in MFS mice. The increased inflammation response and matrix metalloproteinases activities were also attenuated by C3aRA treatment in MFS mice. Therefore, these findings indicate that the complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.
Insights
In Marfan syndrome, blocking the complement C3a/C3aR pathway reduced aortic aneurysm development. This targeted approach offers a potential therapeutic strategy for this cardiovascular complication.
Area of Science:
- Cardiovascular Biology
- Immunology
- Genetics
Background:
- Marfan syndrome (MFS), caused by fibrillin 1 (FBN1) mutations, frequently leads to thoracic aortic aneurysm (TAA).
- The complement system is implicated in aortic aneurysm formation, but its specific role in MFS-associated TAA is not fully understood.
Purpose of the Study:
- To investigate the involvement of the complement system, particularly C3a and its receptor (C3aR), in the pathogenesis of MFS-associated TAA.
- To evaluate the therapeutic potential of inhibiting the C3a/C3aR pathway in MFS mice.
Main Methods:
- Quantification of complement factors (C3a, C5a, C3b/iC3b) in plasma and aortic tissue of MFS patients and mice.
- Assessment of C3a receptor (C3aR) expression in MFS aortas.
- In vitro studies using recombinant C3a on macrophages.
- Administration of a C3aR antagonist (C3aRA) to MFS mice to assess its effects on TAA development, inflammation, and matrix metalloproteinases (MMPs) activity.
Main Results:
- Elevated levels of C3a and C5a were observed in MFS patients and mice.
- Increased deposition of C3b/iC3b was found in the aortic tissue of MFS mice, correlating with elastic fiber rupture.
- C3aRA treatment attenuated TAA progression, reduced inflammation, and decreased MMP activity in MFS mice.
Conclusions:
- The complement C3a/C3aR axis is activated in Marfan syndrome and contributes to thoracic aortic aneurysm formation.
- Inhibition of C3a/C3aR signaling represents a promising therapeutic strategy for mitigating aortic aneurysm development in MFS.
