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No prominent role for complement C1-esterase inhibitor in Marfan syndrome mice
Stijntje Hibender1,2, Siyu Li1,2, Alex V Postma2,3,4
1Amsterdam UMC Location University of Amsterdam, Department of Medical Biochemistry, Meibergdreef, Amsterdam, The Netherlands.
Abstract:
Marfan syndrome (MFS) is a connective tissue disorder causing aortic aneurysm formation. Currently, only prophylactic aortic surgery and blood pressure-lowering drugs are available to reduce the risk of aortic rupture. Upon whole genome sequencing of a Marfan family, we identified a complement gene C1R variant (p.Ser152Leu), which is associated with severe aortic patients. Therefore, we assessed the role of complement activation in MFS aortic tissue. Expression of various complement genes and proteins was detected in human and murine MFS aneurysm tissue, which prompted us to study complement inhibition in MFS mice. Treatment of the Fbn1C1041G/+ MFS mice with human plasma-derived C1-esterase inhibitor Cetor® resulted in reduced complement deposition, decreased macrophage influx in the aorta, and lower circulating TNFα levels. However, in line with previous anti-inflammatory treatments, complement inhibition did not change the aortic dilatation rate in this MFS mouse model. Thus, while complement factors/component 3 activation were detected in human/murine MFS aorta, Cetor® had no effect on aortic dilatation in MFS mice, indicating that complement inhibition is not a suitable treatment strategy in MFS.
Insights
Complement activation is detected in Marfan syndrome (MFS) aortic tissue, but inhibiting it with Cetor® did not prevent aortic enlargement in MFS mice. This suggests complement inhibition is not a viable treatment for Marfan syndrome aortic disease.
Area of Science:
- Cardiovascular Research
- Genetics
- Immunology
Background:
- Marfan syndrome (MFS) is a genetic connective tissue disorder leading to aortic aneurysm and rupture.
- Current treatments for MFS focus on surgical repair and blood pressure management.
- A novel complement gene C1R variant was linked to severe aortic disease in MFS patients.
Purpose of the Study:
- To investigate the role of complement system activation in Marfan syndrome-associated aortic disease.
- To evaluate the therapeutic potential of complement inhibition in an MFS mouse model.
Main Methods:
- Whole genome sequencing identified a C1R variant in an MFS family.
- Complement gene and protein expression was analyzed in human and murine MFS aortic tissue.
- MFS mice (Fbn1C1041G/+) were treated with C1-esterase inhibitor (Cetor®).
- Assessed complement deposition, macrophage infiltration, TNFα levels, and aortic dilatation.
Main Results:
- Complement gene and protein expression was elevated in MFS aortic tissue.
- Cetor® treatment reduced complement deposition, macrophage influx, and TNFα levels in MFS mice.
- Complement inhibition did not alter the rate of aortic dilatation in MFS mice.
Conclusions:
- Complement activation occurs in the aorta during Marfan syndrome.
- Inhibition of complement component C1 with Cetor® does not prevent aortic dilatation in MFS mice.
- Complement inhibition is unlikely to be an effective therapeutic strategy for Marfan syndrome aortic disease.
