Abstract 254: Sirtuin-1 Activation Has no Effect on Aortic Root Dilatation in Marfan Mice

Rationale: Marfan syndrome (MFS) is an autosomal connective tissue disorder caused by mutations in the Fibrillin-1 (FBN1) gene. MFS 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. Losartan has been shown to inhibit aortic root dilatation in MFS patients. The beneficial effect of losartan suggests the detrimental involvement of angiotensin II receptor 1 (AT1R) signaling as a cause for aortic pathology. Angiotensin II (Ang-II) can induce cellular senescence, and downregulates sirtuin-1 (SIRT-1) expression. SIRT-1 is an NAD-dependent deacetylase which can prevent senescence. Among other functions, resveratrol can activate SIRT-1 and is effective in inhibiting aortic root dilatation in MFS mice. To further delineate the underlying mechanism, SIRT-1 activator SRT1720 is examined as therapeutic in MFS mice. Methodology: In the current study we investigated the effect of SRT1720 on aortic root dilatation in the Fbn1 C1039G/+ MFS mouse model. Eight week old mice were treated for two months with SRT1720. Aortic senescence and aortic root diameters were measured. Results: Effectiveness of the compound was established by measurement of body weight and granulocyte blood count. As expected, SRT1720-treated MFS mice showed decreased weight gain and increased granulocyte counts, confirming that SRT1720 was effective. While aortic senescence was decreased in the SRT1720-treated mice, this had no beneficial effect on aortic root dilatation. Conclusions: While SRT1720 prevented aortic senescence, this did not have an effect on aortic root dilatation in MFS mice. Thus the beneficial effect of resveratrol on aortic root dilatation can not be explained via its function as SIRT-1 activator.