BACKGROUND Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation. METHODS The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in Sting-deficient (Stinggt/gt) mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro. RESULTS In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, Stinggt/gt mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged Stinggt/gt mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development. CONCLUSIONS Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.

中文翻译：

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胞浆DNA及其传感适配器STING在主动脉变性，解剖和破裂中的关键作用。

背景技术由进行性主动脉平滑肌细胞（SMC）损失和细胞外基质降解引起的散发性主动脉瘤和夹层（AAD）是高度致死性疾病。确定驱动主动脉变性的机制是开发有效的药物治疗以预防疾病进展的关键步骤。最近的证据表明，胞质DNA和胞质DNA传感适配器STING（干扰素基因的刺激物）的异常激活在血管炎症和破坏中起关键作用。在这里，我们检查了该机制在主动脉变性和偶发AAD形成中的作用。方法在散发性升主胸AAD患者的主动脉组织中检查主动脉细胞中胞质DNA的存在和STING途径的激活。在散发性AAD模型中，通过挑战高脂饮食和血管紧张素II的组合，在散发性AAD模型中评估了Sting缺陷（Stinggt / gt）小鼠中STING在AAD发育中的作用。我们还检查了STING对体外SMC死亡和巨噬细胞活化的直接影响。结果在人零星的AAD组织中，我们观察到SMC和巨噬细胞中存在胞质DNA以及STING通路的显着激活。在散发的AAD模型中，Stinggt / gt小鼠在胸主动脉和腹主动脉区域均显示出挑战性诱发的主动脉扩张，解剖和破裂明显减少。单细胞转录组分析显示，野生型小鼠的主动脉攻击可诱导SMC中的DNA损伤反应，炎症反应，去分化和细胞死亡，和基质金属蛋白酶在巨噬细胞中的表达。这些变化在受攻击的Stinggt / gt小鼠中减弱。从机制上讲，SMC中的核和线粒体DNA损伤以及随后的DNA泄漏到细胞质中激活了STING信号传导，从而通过凋亡和坏死性细胞死亡导致细胞死亡。此外，受损的SMC中的DNA被巨噬细胞吞噬，巨噬细胞在其中激活了STING及其靶干扰素调节因子3，后者直接诱导了基质金属蛋白酶9的表达。我们还发现，在药理上抑制STING活化可部分阻止AAD的发展。