No prominent role for complement C1-esterase inhibitor in Marfan syndrome mice

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 for aortic rupture. Upon whole genome sequencing (WGS) of a Marfan family, we identified a complement gene C1R variant (p.Ser152Leu), which associated with the 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 aortic dilatation rate in this MFS mouse model. Thus, while complement factors/C3 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.

Uncovering the Hidden World of Aqueous Humor Proteins for Discovery of Biomarkers for Marfan Syndrome

“…Recent research on aortic aneurysms in MFS indicates that the progression of aneurysms may involve extracellular matrix remodeling, cell adhesion, and complement activation. [49][50][51][52] In 2022, Stijntje Hibender et al detected a complement gene C1R variant linked to aortic comorbidity through whole-genome sequencing (WGS) on a Marfan family. [51] A single-cell RNA sequencing workflow applied to aortic aneurysm samples collected in Fbn1C1041G/+ (MFS) mice and controls reported a cluster of altered genes involved in extracellular matrix modulation, collagen synthesis, and adhesion.…”

“…[49][50][51][52] In 2022, Stijntje Hibender et al detected a complement gene C1R variant linked to aortic comorbidity through whole-genome sequencing (WGS) on a Marfan family. [51] A single-cell RNA sequencing workflow applied to aortic aneurysm samples collected in Fbn1C1041G/+ (MFS) mice and controls reported a cluster of altered genes involved in extracellular matrix modulation, collagen synthesis, and adhesion. [52] In our study, through functional enrichment analysis of DEPs in AH and lens tissue, we discovered that MFS patients with lens dislocation exhibit significant dysregulation of complement and coagulation-related functions in AH.…”

“…Recent research on aortic aneurysms in MFS indicates that the progression of aneurysms may involve extracellular matrix remodeling, cell adhesion, and complement activation. [ 49–52 ] In 2022, Stijntje Hibender et al. detected a complement gene C1R variant linked to aortic comorbidity through whole‐genome sequencing (WGS) on a Marfan family.…”