No Beneficial Effect of General and Specific Anti-Inflammatory Therapies on Aortic Dilatation in Marfan Mice

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.

Resveratrol Inhibits Aortic Root Dilatation in the Fbn1 C1039G/+ Marfan Mouse Model

“…In line with these observations, we demonstrated that anti-inflammatory medication diminishes vascular inflammation, yet it did not reduce aortic root dilatation. 39 One may speculate that not the number of inflammatory cells is relevant but that the type of inflammatory cells in the vasculature is decisive on aortic growth outcome.…”

Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome

“…FBN1 mutations in all Marfan patients by genetic specialists to predict individual losartan effectiveness. Moreover, enhanced effort should be made to further characterize the Marfan patients with dominant negative FBN1 mutations 23 to find novel therapeutics reducing aortic dilatation rate for this patient population.…”

TGF-β Signaling in Control of Cardiovascular Function

“…This beneficial effect of losartan on aortic dilatation is supported by the results of a phase III clinical trial in patients with MFS (Groenink et al 2013). Finally, doxycycline, an anti-inflammatory agent and matrix metalloproteinase (MMP) inhibitor, also reduces aortic root dilation in MFS mice by inhibiting TGF-b-induced MMP activation and MMP-induced release of TGF-b (Xiong et al 2008;Lindeman et al 2009), but not by reducing inflammation (Chung et al 2008;Franken et al 2014).…”