Vascular Biology Section (E.B., S.S.P.D.L., Y.T., H.L., Y.H., Y.W., P.M.S., X.Y., J.B.G., X.W., J.H., F.S.), Department of Medicine, Boston University Chobenian & Avedisian School of Medicine, MA.
Renal Section (V.C.), Department of Medicine, Boston University Chobenian & Avedisian School of Medicine, MA.
Arterioscler Thromb Vasc Biol. 2023 Aug;43(8):e339-e357. doi: 10.1161/ATVBAHA.123.319145. Epub 2023 Jun 8.
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).
In this study, we investigated whether redox dysregulation of SirT1 contributed to the pathogenesis of TAA using fibrillin-1 hypomorphic mice (Fbn1), an established model of Marfan syndrome prone to aortic dissection/rupture.
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 Fbn1 mice, before induction of severe oxidative stress markers. Fbn1 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 Fbn1 aortas, stimulated rOPTM of SirT1, decreasing its deacetylase activity in VSM cells. VSM cell-specific deletion of SirT1 in Fbn1 mice (SMKO-Fbn1) caused a dramatic increase in aortic MMP2 expression and worsened TAA progression, leading to aortic rupture in 50% of SMKO-Fbn1 mice, compared with 25% of Fbn1 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.
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.
胸主动脉瘤（TAAs）是主动脉异常扩张，也是马凡综合征的一种主要心血管并发症。我们之前证明血管平滑肌（VSM）SirT1（沉默调节蛋白-1）作为一种赖氨酸去乙酰化酶，对于与慢性氧化应激和基质金属蛋白酶（MMPs）异常激活相关的适应性不良的主动脉重构具有关键作用。
在这项研究中，我们使用纤维连接蛋白 1 低功能型（Fbn1）小鼠（马凡综合征的一种易于发生主动脉夹层/破裂的已建立的模型）来研究 SirT1 的氧化还原失调是否有助于 TAA 的发病机制。
马凡综合征患者的主动脉中氧化应激标志物 3-硝基酪氨酸和 4-羟基壬烯醛显著升高。此外，在 Fbn1 小鼠的主动脉中，蛋白质半胱氨酸的可逆氧化翻译后修饰（rOPTM），特别是 S-谷胱甘肽化，在严重氧化应激标志物诱导之前就显著增加。Fbn1 主动脉和 VSM 细胞中 SirT1 的 rOPTM 增加，同时伴有乙酰化蛋白的上调，这是 SirT1 活性降低的指标，以及 MMP2/9 活性的增加。从机制上讲，我们证明 TGFβ（转化生长因子β）在 Fbn1 主动脉中增加，刺激 SirT1 的 rOPTM，降低其在 VSM 细胞中的去乙酰化酶活性。在 Fbn1 小鼠中特异性删除 VSM 细胞中的 SirT1（SMKO-Fbn1）导致 MMP2 在主动脉中的表达显著增加，并且 TAA 进展恶化，导致 50%的 SMKO-Fbn1 小鼠发生主动脉破裂，而 Fbn1 小鼠的这一比例为 25%。在 VSM 细胞中，SirT1 的 rOPTM、rOPTM 介导的 SirT1 活性抑制以及 MMP2/9 活性增加，都因 Glrx（谷胱甘肽还原酶-1）的缺失而恶化，Glrx 或氧化抗性 SirT1 突变体在 VSM 细胞中的过表达则纠正了这些现象。
我们的新发现强烈表明，SirT1 的 S-谷胱甘肽化在 TAA 的发病机制中起因果作用。预防或逆转 SirT1 的 rOPTM 可能是一种预防马凡综合征患者 TAA 和 TAA 夹层/破裂的新型治疗策略，目前尚无针对该疾病的靶向治疗方法。
