No beneficial effect of general and specific anti-inflammatory therapies on aortic dilatation in Marfan mice.

Romy Franken,Barbara J M Mulder,Aeilko H Zwinderman,Stijntje Hibender,Carlie J M De Vries,Maarten Groenink,Alexander W Den Hartog,Vivian De Waard,Teodora Radonic,Esther Lutgens

doi:10.1371/journal.pone.0107221

Romy Franken, Barbara J M Mulder + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0107221

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Abstract

AimsPatients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. In the FBN1 C1039G/+ Marfan mouse model, losartan decreases aortic root dilatation. We recently confirmed this beneficial effect of losartan in adult patients with Marfan syndrome. The straightforward translation of this mouse model to man is reassuring to test novel treatment strategies. A number of studies have shown signs of inflammation in aortic tissue of Marfan patients. This study examined the efficacy of anti-inflammatory therapies in attenuating aortic root dilation in Marfan syndrome and compared effects to the main preventative agent, losartan.Methods and ResultsTo inhibit inflammation in FBN1 C1039G/+ Marfan mice, we treated the mice with losartan (angiotensin II receptor type 1 inhibitor), methylprednisolone (corticosteroid) or abatacept (T-cell-specific inhibitor). Treatment was initiated in adult Marfan mice with already existing aortic root dilatation, and applied for eight weeks. Methylprednisolone- or abatacept-treated mice did not reveal a reduction in aortic root dilatation. In this short time frame, losartan was the only treatment that significantly reduced aorta inflammation, transforming growth factor-beta (TGF-β) signaling and aortic root dilatation rate in these adult Marfan mice. Moreover, the methylprednisolone-treated mice had significantly more aortic alcian blue staining as a marker for aortic damage.ConclusionAnti-inflammatory agents do not reduce the aortic dilatation rate in Marfan mice, but possibly increase aortic damage. Currently, the most promising therapeutic drug in Marfan syndrome is losartan, by blocking the angiotensin II receptor type 1 and thereby inhibiting pSmad2 signaling.

Highlights

Marfan syndrome is a monogenic connective tissue disorder, caused by mutations in the gene encoding fibrillin-1 (FBN1) [1]
To inhibit inflammation in FBN1C1039G/+ Marfan mice, we treated the mice with losartan, methylprednisolone or abatacept (T-cell-specific inhibitor)
Methylprednisoloneor abatacept-treated mice did not reveal a reduction in aortic root dilatation

Summary

Introduction

Marfan syndrome is a monogenic connective tissue disorder, caused by mutations in the gene encoding fibrillin-1 (FBN1) [1]. In a well-known Marfan mouse model with a cysteine substitution in FBN1 (C1039G), losartan effectively inhibits aortic root dilatation by blocking the angiotensin II type 1 receptor (AT1R), and thereby the downstream production of transforming growth factor (TGF)-b [7]. The destructive role for TGF-b was confirmed since neutralizing TGF-b antibodies inhibited aortic root dilatation in Marfan mice and inhibited the activation of TGF-b-downstream transcription factor Smad2 [7]. Increased Smad activation is usually observed in human Marfan aortic tissue and considered crucial in the pathology of aortic degeneration [8]. Even though the response to losartan was highly variable, we recently confirmed the overall beneficial effect of losartan on aortic dilatation in a cohort of 233 human adult Marfan patients [9]. The direct translation of this therapeutic approach from the Marfan mouse model to the clinic, exemplifies the extraordinary power of this mouse model to test novel treatment strategies, which are still necessary to achieve optimal personalized care

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Conclusion