Redox Dysregulation Of Vascular Smooth Muscle Sirtuin-1 In Marfan Syndrome

Background: Thoracic aortic aneurysms and dissections (TAAD) are life-threatening aortic conditions and a major cardiovascular complication of Marfan syndrome (MFS). We previously demonstrated that vascular smooth muscle sirtuin-1 (Sirt1), a lysine deacetylase, protects against aortic dissection by suppressing aberrant activation of matrix metalloproteinases (MMP2/9). Objective: In this study, we investigated whether Sirt1’s dysregulation contributed to TAAD in MFS. Approach & Results: Our results showed that oxidative stress markers (3-nitrotyrosine and 4-hydroxy-2-nonenal) were significantly elevated in aortas of MFS patients, compared to healthy controls. Similarly, reversible oxidative post-translational modifications (rOPTM) of protein cysteines, mainly S-glutathionylation, were dramatically increased in aortas of fibrillin-1 hypomorphic mice (Fbn1 mgR/mgR ), an established model of MFS prone to aortic dissection/rupture. We found that Sirt1 was one of these oxidatively modified proteins in Fbn1 mgR/mgR aortas and smooth muscle cells (VSMCs). rOPTM of Sirt1 resulted in decreased Sirt1 activity, measured as levels of acetylated p53 and histone 3, and increased MMP2/9 activity, measured by in gel-zymography and in situ, in VSMCs and aortas. Deletion of glutaredoxin-1 (Glrx), a specific de-glutathionylation enzyme, increased rOPTM of Sirt1, rOPTM-mediated inhibition of Sirt1 activity, and MMP2/9 activity in VSMCs. On the contrary, overexpression of Glrx or of an oxidation-resistant Sirt1 mutant with an AAV prevented these changes in VSMCs. Lastly, VSMC-specific deletion of Sirt1 in Fbn1 mgR/mgR (SMKO- Fbn1 mgR/mgR ) mice significantly worsened TAAD progression leading to aortic rupture in 50% of SMKO-Fbn1 mgR/mgR mice, compared to 25% of Fbn1 mgR/mgR mice. Conclusions: Our results strongly suggest that preventing rOPTM of Sirt1, thereby preserving its activity, may be a novel therapeutic strategy to prevent TAAD in individuals with MFS, for which currently no targeted therapies are available.