1. Redox Dysregulation of Vascular Smooth Muscle Sirtuin-1 in Thoracic Aortic Aneurysm in Marfan Syndrome.
- Author
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Budbazar E, Sulser Ponce De Leon S, Tsukahara Y, Liu H, Huangfu Y, Wang Y, Seabra PM, Yang X, Goodman JB, Wan X, Chitalia V, Han J, and Seta F
- Subjects
- Mice, Animals, Matrix Metalloproteinase 2 metabolism, Fibrillins metabolism, Muscle, Smooth, Vascular metabolism, Sirtuin 1 genetics, Sirtuin 1 metabolism, Microfilament Proteins metabolism, Fibrillin-1 genetics, Fibrillin-1 metabolism, Transforming Growth Factor beta metabolism, Oxidation-Reduction, Disease Models, Animal, Glutaredoxins metabolism, Glutaredoxins therapeutic use, Marfan Syndrome complications, Marfan Syndrome genetics, Marfan Syndrome metabolism, Aortic Aneurysm, Thoracic genetics, Aortic Aneurysm, Thoracic prevention & control, Aortic Rupture prevention & control
- Abstract
Background: Thoracic aortic aneurysms (TAAs) are abnormal aortic dilatations and a major cardiovascular complication of Marfan syndrome. We previously demonstrated a critical role for vascular smooth muscle (VSM) SirT1 (sirtuin-1), a lysine deacetylase, against maladaptive aortic remodeling associated with chronic oxidative stress and aberrant activation of MMPs (matrix metalloproteinases)., Methods: In this study, we investigated whether redox dysregulation of SirT1 contributed to the pathogenesis of TAA using fibrillin-1 hypomorphic mice (Fbn1
mgR/mgR ), an established model of Marfan syndrome prone to aortic dissection/rupture., Results: Oxidative stress markers 3-nitrotyrosine and 4-hydroxynonenal were significantly elevated in aortas of patients with Marfan syndrome. Moreover, reversible oxidative post-translational modifications (rOPTM) of protein cysteines, particularly S-glutathionylation, were dramatically increased in aortas of Fbn1mgR/mgR mice, before induction of severe oxidative stress markers. Fbn1mgR/mgR aortas and VSM cells exhibited an increase in rOPTM of SirT1, coinciding with the upregulation of acetylated proteins, an index of decreased SirT1 activity, and increased MMP2/9 activity. Mechanistically, we demonstrated that TGFβ (transforming growth factor beta), which was increased in Fbn1mgR/mgR aortas, stimulated rOPTM of SirT1, decreasing its deacetylase activity in VSM cells. VSM cell-specific deletion of SirT1 in Fbn1mgR/mgR mice (SMKO-Fbn1mgR/mgR ) caused a dramatic increase in aortic MMP2 expression and worsened TAA progression, leading to aortic rupture in 50% of SMKO-Fbn1mgR/mgR mice, compared with 25% of Fbn1mgR/mgR mice. rOPTM of SirT1, rOPTM-mediated inhibition of SirT1 activity, and increased MMP2/9 activity were all exacerbated by the deletion of Glrx (glutaredoxin-1), a specific deglutathionylation enzyme, while being corrected by overexpression of Glrx or of an oxidation-resistant SirT1 mutant in VSM cells., Conclusions: Our novel findings strongly suggest a causal role of S-glutathionylation of SirT1 in the pathogenesis of TAA. Prevention or reversal of SirT1 rOPTM may be a novel therapeutic strategy to prevent TAA and TAA dissection/ruptures in individuals with Marfan syndrome, for which, thus far, no targeted therapy has been developed., Competing Interests: Disclosures None.- Published
- 2023
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