Critical Role of Cytosolic DNA and Its Sensing Adaptor STING in Aortic Degeneration, Dissection, and Rupture

Abstract

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 ( Sting gt/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, Sting gt/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 Sting gt/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.

MKL1 cooperates with p38MAPK to promote vascular senescence, inflammation, and abdominal aortic aneurysm

“…E, Representative confocal microscopy images for immunofluorescence staining of the indicated proteins in cross-sections of the thoracic aortas from C57BL/6 mice infused with high fat diet (HFD) with Ang II or saline for 4 weeks (n = 3). F, Dot plot graph from single-cell RNA-sequencing analysis [ 27 ] in aortas of C57BL/6 mice fed with HFD plus Ang II infusion vs C57BL/6 mice fed with chow diet without Ang II infusion (n = 3, pooled). The size of circle represents the percent of cells expressing Mkl1 in each cluster; the color scale indicates the expression level.…”

“…Human abdominal aortic tissue specimens were provided by the Munich Vascular Biobank from patients undergoing elective open AAA repair and organ donors (kidney transplant surgery) [ 26 ]. Human ascending thoracic aortic aneurysm and dissection and control normal aortic segments were from our existing aortic tissue bank as described in our recent publication [ 27 ], respectively. The related protocols were approved by the Institutional Review Board (IRB) at the Klinikum rechts der Isar of the Technical University Munich and Baylor College of Medicine, respectively.…”

“…Heatmap was illustrated using the raw count value of all related transcripts and presented as the log transformation of the normalized raw count data. Mkl1 gene expression in different cell clusters in control versus aneurysmal aortas induced by Ang II infusion combined with high fat diet, was based on our recently published single cell RNA-seq study [ 27 ]. We used dimensional reduction and shared nearest neighbor (SNN) modularity clustering algorithm to assess cell population deconvolution.…”

Kawasaki-like diseases and thrombotic coagulopathy in COVID-19: delayed over-activation of the STING pathway?

“…Over-activation of the STING-pathway, could increase the risk of delayed aneurysms not only in KD but also COVID-19 vasculitis. Indeed: 1-even incomplete form of KD (KD-like disorders) can lead to severe, and sometimes lethal, delayed aneurysms; 2-the STING pathway is activated in aortic aneurysms, especially those induced by infections, and it contributes to their pathogenesis [33]. As giant coronary aneurysms in children with KD can regress following the use of anti-cytokines [21], drugs inhibiting the cytokine storm occurring in severe COVID-19 might be also useful to prevent the delayed onset of similar coronary or cerebral aneurysms, either in children with KD-like features and/or adults with COVID-19.…”

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

“…Stimulator of interferon genes (STING) is a cytosolic DNA sensor wildly distributed in mammalian immune cells, including DC cell, T cells, and macrophage, that functions as an important mediator to regulate innate immune response [13]. Generally, cyclic GMP-AMP synthase (cGAS) catalyzes cytosolic DNA including the foreign double-stranded DNA (dsDNA) derived from pathogens and endogenous chromosomal fragments leakaged from mitochondria into cyclic GMP-AMP (cGAMP).…”