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


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          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 Fbn1 C1041G/+ 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.

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          Most cited references48

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          The GTEx Consortium atlas of genetic regulatory effects across human tissues

          The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
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            2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC).

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              Complement: a key system for immune surveillance and homeostasis.

              Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.

                Author and article information

                Vasc Biol
                Vasc Biol
                Vascular Biology
                Bioscientifica Ltd (Bristol )
                24 October 2022
                01 February 2022
                : 4
                : 1
                : 40-49
                [1 ]Amsterdam UMC Location University of Amsterdam , Department of Medical Biochemistry, Meibergdreef, Amsterdam, The Netherlands
                [2 ]Amsterdam Cardiovascular Sciences , Atherosclerosis & Ischemic Syndromes, Amsterdam, The Netherlands
                [3 ]Amsterdam UMC Location University of Amsterdam , Department of Medical Biology, Meibergdreef, Amsterdam, The Netherlands
                [4 ]Amsterdam UMC Location University of Amsterdam , Department of Human Genetics, Meibergdreef, Amsterdam, The Netherlands
                [5 ]Sanquin Research , Department of Immunopathology, Plesmanlaan, Amsterdam, The Netherlands
                [6 ]Amsterdam UMC Location University of Amsterdam , Landsteiner Laboratory, Meibergdreef, Amsterdam, The Netherlands
                [7 ]Amsterdam UMC Location University of Amsterdam , Department of Pathology, Meibergdreef, Amsterdam, The Netherlands
                [8 ]Amsterdam UMC Location University of Amsterdam , Heart Center, Department of Cardiothoracic Surgery, Meibergdreef, Amsterdam, The Netherlands
                Author notes
                Correspondence should be addressed to V de Waard: v.dewaard@ 123456amsterdamumc.nl
                Author information
                © The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                : 13 July 2022
                : 24 October 2022

                aortic aneurysm,complement inhibition,inflammation,marfan syndrome,whole genome sequencing


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