A STAT1-GBP3-STING positive feedback loop governs inflammation, oxidative stress, and DNA damage to trigger acute aortic dissection [scRNA-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE303634 | GEO | 2026/01/28
REPOSITORIES: GEO
Similar Datasets
Project description: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.
2025-09-30 | GSE214595 | GEO
Project description:In this study, we aim to investigate the role of vascular smooth muscle cell (VSMC) NFATc3 in the development of AAD and establish NFATc3 as a novel target to treat AAD. We used VSMC-specific NFATc3 knockout mice in AAD model of BAPN treatment. The molecular mechanisms underlying NFATc3 function were investigated using RNA-seq analysis on aortas with BAPN treatment.
2025-07-30 | GSE234349 | GEO
Project description:A STAT1-GBP3-STING positive feedback loop governs inflammation, oxidative stress, and DNA damage to trigger acute aortic dissection [scRNA-Seq]
| PRJNA1295966 | ENA
Project description:<p>Aortic disease poses a significant mortality risk in adults, yet many of its underlying factors remain undiscovered. In this study, we identify mitochondrial NAD⁺ deficiency as a causal factor. Metabolomics analysis of 73 surgical aortic specimens revealed impaired NAD⁺ salvage and mitochondrial transport in diseased aortas. Precursor metabolites NMN and NAM were significantly elevated, while NAD⁺ levels were decreased, indicating a disrupted salvage biosynthesis pathway. Using mouse models, we provided mechanistic insights into the pathogenic process. The production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid in collagen. A deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, impairs proline biosynthesis in mitochondria, potentially contributing to the progression of aortic disease.</p>
2024-12-04 | MTBLS8062 | MetaboLights
Project description:Acute aortic dissection (AAD) is one of the major aortic diseases that occurs without a preceding symptom and often results in sudden death. Despite the recent advances in cardiovascular medicine, AAD remains a serious problem because its molecular pathogenesis is largely unknown. In this paper, we report our serendipitous discovery that stress-induced expression of tenascin C (TNC), a member of matricellular proteins, is the protection mechanism of aorta to prevent AAD. The aortic wall stress imposed by the aortic stiffening and the angiotensin II infusion caused the strong induction of TNC in wild type mouse aorta without gross morphological changes. While TNC knockout mice at the baseline showed no morphological, histological or biomechanical abnormalities of aorta, deletion of TNC gene rendered the aorta susceptible to AAD upon the aortic stress. The stressed TNC-null aorta showed the loss of the tensile strength due to the insufficient expression of extracellular matrix proteins and the exaggerated proinflammatory response before the onset of AAD. Therefore, TNC works as a stress-activated molecular damper both by reinforcing the tensile strength and by limiting the excessive proinflammatory response in aorta. Thus far, the molecular event that leads to the AAD development has been unclear because of the unpredictable nature of the AAD onset. This study sheds light on the previously unrecognized tissue protection mechanism that converts the potentially harmful stress response into the active reinforcement of the aorta, of which failure leads to the development of AAD. Although TNC is expressed in various tissues upon the mechanical and proinflammatory stimuli, its role has long been a mystery. Our data uncovered the adaptive role of TNC in aorta that must be resilient to the continuous hemodynamic and humoral stress for lifetime.
2015-03-27 | GSE36899 | GEO
Project description:The phenotypic switch of vascular smooth muscle cells (VSMCs) is a crucial pathogenesis in aortic aneurysm and dissection (AAD), metabolic remodeling from oxidative phosphorylation (OXPHOS) to glycolysis involved in the process. Histone lactylation expression was analyzed in aorta of aortic aneurysm (AA) patients and AAD mice, as well as the AngII(angiotensin II)-treated VSMCs. CUT&Tag was used to explore the downstream target gene for H4K16 lactylation (H4K16la) between AngII-induced VSMCs and Control. The finding was to explore the impact of histone lactylation (H4K16la) on the progress of AAD.
2026-02-12 | GSE301206 | GEO
Project description:Aortic aneurysm and dissection (AAD) is a life-threatening disease without effective pharmacological treatments. The progressive loss of vascular smooth muscle cells (VSMCs) is the fundamental pathophysiological basis for AAD, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for maintenance of VSMC homeostasis and consequent prevention of vascular remodeling-related diseases. However, its role in AAD development requires further investigation. Here, we show that SIRT6 expression was significantly reduced in VSMCs of the thoracic aorta in AAD patients. Sirt6 deficiency in VSMCs dramatically accelerated angiotensin Ⅱ (Ang Ⅱ) infusion-induced AAD formation and rupture even without an Apoe-deficient background. In vitro studies demonstrated that Sirt6 deficiency led to mitochondrial dysfunction and accelerated VSMC senescence. Mechanistically, SIRT6 could bind and deacetylate NRF2, a key transcription factor for mitochondrial biogenesis, however, Sirt6 deficiency inhibited NRF2 and reduced mRNAs encoding mitochondrial complex. Notably, MDL-811, a newly developed small-molecule SIRT6 agonist, effectively reversed Ang Ⅱ-induced mitochondrial dysfunctions in human aortic smooth muscle cells. More importantly, MDL-811 also mitigated AAD progression in mice. These findings suggest that SIRT6 plays a protective role in AAD development and targeting SIRT6 with small-molecule activators such as MDL-811 could represent a promising therapeutic strategy for AAD.
2025-03-07 | GSE290902 | GEO
Project description:Aortic tissues of developing and established aneurysms produced by angiotensin II (AngII) infusion were examined in Apoe-/- and Ldlr-/- mice. Aortas were also acquired from wildtype C57BL/6J mice following intraluminal elastase incubation. Aortas were dissected free and separated into eight anatomical segments for proteomics in comparison to their appropriate controls. In addition, proteomics was performed on human infrarenal aortic aneurysm tissues as well as aortic tissue collected from age-matched controls.
2022-08-02 | PXD032293 | Pride
Project description:Acute aortic dissection (AAD) is one of the major aortic diseases that occurs without a preceding symptom and often results in sudden death. Despite the recent advances in cardiovascular medicine, AAD remains a serious problem because its molecular pathogenesis is largely unknown. In this paper, we report our serendipitous discovery that stress-induced expression of tenascin C (TNC), a member of matricellular proteins, is the protection mechanism of aorta to prevent AAD. The aortic wall stress imposed by the aortic stiffening and the angiotensin II infusion caused the strong induction of TNC in wild type mouse aorta without gross morphological changes. While TNC knockout mice at the baseline showed no morphological, histological or biomechanical abnormalities of aorta, deletion of TNC gene rendered the aorta susceptible to AAD upon the aortic stress. The stressed TNC-null aorta showed the loss of the tensile strength due to the insufficient expression of extracellular matrix proteins and the exaggerated proinflammatory response before the onset of AAD. Therefore, TNC works as a stress-activated molecular damper both by reinforcing the tensile strength and by limiting the excessive proinflammatory response in aorta. Thus far, the molecular event that leads to the AAD development has been unclear because of the unpredictable nature of the AAD onset. This study sheds light on the previously unrecognized tissue protection mechanism that converts the potentially harmful stress response into the active reinforcement of the aorta, of which failure leads to the development of AAD. Although TNC is expressed in various tissues upon the mechanical and proinflammatory stimuli, its role has long been a mystery. Our data uncovered the adaptive role of TNC in aorta that must be resilient to the continuous hemodynamic and humoral stress for lifetime. We used periaortic application of 0.5 M CaCl2 to the infrarenal aorta or either wild type (WT) or tenascin C knockout (TNC-KO) mice to create the mouse model for stiffened aorta and infused the mice with AngII (1 µg/min/kg) for 1 week to apply the pathological stress on aorta (Ca+AngII). Mice were then killed with an overdose of pentobarbital to obtain the tissue samples. The suprarenal aortic samples, from the level of right renal artery to 10 mm above the right renal artery, and infrarenal aortic samples, from the level of left renal artery to 10 mm below the left renal artery, were collected and kept in RNAlater (Qiagen) until the extraction of total RNA using RNeasy (Qiagen). We obtained the RNA samples from 8 mice with Ca+AngII treatment and 5 mice without Ca+AngII treatment for each genotype. We pooled the RNA samples with the identical experimental condition to perform the transcriptome analysis using Mouse Genome 430 2.0 (Affymetrix). We obtained suprarenal aortic smooth muscle cells (ASMCs) from TNC-KO mice by enzymatic dispersion and cultured them in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum. We cultured TNC-KO ASMCs in the presence or absence of exogenous TNC (10 µg/mL) and stimulated the cells with 10 ng/mL TNF-alpha for 24 h before obtaining total RNA using RNeasy. We used 3 independent ASMC cultures without the exogenous TNC and 4 independent cultures with the exogenous TNC. We hybridized each of the RNA samples individually to Mouse Genome 430 2.0 Array (Affymetrix).
2015-03-27 | E-GEOD-36899 | biostudies-arrayexpress
Project description:The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. We found that miR-1204 was significantly increased in both plasma and aorta of elder patients with AAD, and was positively correlated with age. Cell senescence induced the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induced vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop.
2024-04-02 | GSE255157 | GEO