Abstract 487: Resveratrol as an Inhibitor of Aortic Root Dilatation in Marfan Mice

Abstract

Rationale: Marfan syndrome (MFS) is an autosomal connective tissue disorder caused by mutations in the Fibrillin-1 (FBN1) gene. Marfan patients are at risk for aortic aneurysm development and dissection, with often lethal consequences. Treatment consists of aortic root replacement surgery and beta-blocker medication. Recently, losartan was proven to be effective in inhibition of aortic root dilatation in MFS patients. The beneficial effect of losartan suggests the involvement of angiotensin II receptor 1 (AT1R) signaling as a cause for aortic pathology. Angiotensin II (Ang-II) can induce cell senescence, in contrast to sirtuin-1 (SIRT-1), which is an NAD-dependent deacetylase and prevents senescence. Among other functions, resveratrol can activate SIRT-1, which prompted us to investigate the effectiveness of resveratrol treatment in MFS mice. Methodology: In the current study we investigate whether senescence plays a role in aortic dilatation and if resveratrol treatment inhibits aortic root dilatation in the Fbn1 C1039G/+ MFS mouse model. Eight week old mice were treated for two months with resveratrol. Aortic root diameter and senescence were measured. In addition, aortic root pathology was analyzed by different immunohistochemical stainings. Results: Senescence correlates positively with aorta dilatation. Resveratrol inhibits aortic root dilatation, even more efficiently than losartan. The number of inflammatory cells (CD45) and the signaling pathways involving phosphorylated (p-)SMAD2 or p-ERK1/2 are decreased in aortic root sections of losartan treated MFS mice. In contrast, these were not affected in the resveratrol treated MFS mice. Resveratrol did result in a diminished number of elastic lamina breaks and an increased number of nuclear SIRT-1 expressing cells. Conclusions: Senescence is involved in aortic dilatation in MFS mice. Resveratrol efficiently inhibits aortic root dilatation, yet via a different mechanism of action than is considered for losartan, which opens new possibilities for pharmacological treatment of MFS patients.