Transcriptome Sequencing of BAPN-Induced Aortic Dissection in Male and Female Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE325608 | GEO | 2026/07/22
REPOSITORIES: GEO
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Project description:The purpose of this study was to determine whether lysyl oxidase inhibition using β-aminopropionitrile (BAPN) induced region-specific aortopathies in mice. The effects of BAPN were first characterized with regard to dose, strain, age, and sex. Subsequently, BAPN was administered to young male C57BL/6J mice. BAPN-induced aortic rupture predominantly occured or originated in the descending thoracic aorta. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while relatively sporadic in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissection with false lumen formation, macrophage infiltration, collagen deposition, and remodeling of the media and adventitia. Cells surrounding the false lumen were predominantly positive for α-smooth muscle actin. To investigate the molecular basis of the regional heterogeneity, ascending and descending thoracic aortas were harvested after one week of BAPN administration prior to the appearance of overt pathology. BAPN compromised contractile properties in both regions equivalently, while RNA sequencing demonstrated that BAPN altered transcriptomes related to extracellular matrix and cell division differentially between the two regions. In conclusion, BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in young mice.
2023-09-30 | GSE241968 | GEO
Project description:Thoracic aortic dissection (TAD) is a life-threatening acute vascular condition with extremely high morbidity and mortality. Endothelial cells (ECs) are critical for maintaining vascular homeostasis, yet the role of Endothelial-to-Mesenchymal Transition (EndoMT)—a key cell fate process in vascular development and disease—in TAD remains poorly defined. Furthermore, the functional significance of EndoMT-gene-program activation mediated by pyruvate dehydrogenase kinase 4 (PDK4) in TAD has not been elucidated. To explore the mechanistic involvement of EndoMT in TAD, a murine TAD model was established through systemic administration of β-aminopropionitrile (BAPN). RNA sequencing was performed to profile the activation landscape of the EndoMT-gene-program in ECs for identifying key regulatory targets. Concurrently, clinical samples from TAD patients and healthy controls were analyzed to quantify mRNA and protein levels of EndoMT-related markers in aortic tissues. Pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) was identified as a critical regulator and validated as a downstream target of EndoMT signaling using an integrated approach combining RNA-seq, luciferase reporter assays, and immunofluorescent staining. The functional role of Pdk4 in TAD was further validated by using conditional knockout (CKO) mouse model. To facilitate better clinical translation, EC-specific Pdk4 deletion or overexpression mouse models were generated via adeno-associated virus (AAV)-mediated delivery and subjected to TAD model. Serum samples from these mice were collected, and enzyme-linked immunosorbent assay (ELISA) was used to measure levels of endothelial injury markers (sICAM1, sVCAM1, sE-Selectin) for assessing endothelial dysfunction. Additionally, the therapeutic potential of dichloroacetate (DCA), a specific PDK4 inhibitor, was evaluated by administering it to BAPN-fed mice to assess its efficacy in ameliorating TAD progression. A significant upregulation of the EndoMT-gene-program was observed in BAPN-fed murine models of TAD, aortic tissues from TAD patients, and HAECs treated with angiotensin II (Ang II). Administration of AAVEndoPdk4 directly induced TAD formation, which was exacerbated by BAPN co-treatment. Conversely, EC-specific knockdown of Pdk4 reduced TAD formation by inhibiting EndoMT signaling. The same results were also obtained in EC-specific conditional Pdk4 knockout mice (CKO, Pdk4flox/flox; Cdh5-CreERT2). PDK4 was identified as a critical factor in both TAD development and EndoMT process, with SNAI1 transcriptionally activating PDK4; vice versa, PDK4 further enhanced the activation of EndoMT signaling in both in vivo and vitro. PDK4 inhibitor, DCA, significantly slowed TAD progression in BAPN-fed mice. Mechanistically, a PDK4-EndoMT feedback loop was identified in TAD, where interruption of this self-reinforcing pathological cycle markedly attenuates the progression of TAD.
2026-03-27 | GSE314672 | GEO
Project description:Thoracic aortic aneurysm (TAA) is a perilous disease that can lead to aortic dissection (AD), the pathophysiological mechanisms of which remain largely elusive. To improve our understanding of the molecular mechanism underlying TAA, we conducted a tandem mass tag (TMT)-based proteomics analysis and identified two down-regulated proteins, integrin αV, and integrin αL, in serum samples from patients with type A aortic dissection. We confirmed that integrin αV is extensively expressed in the aortic media, and its expression decreases after dissection, whereas the expression of integrin αL showed no significant alteration. Subsequently, by employing a mouse model of TAA induced by β-Aminopropionitrile (BAPN), we discovered that the mice treated with integrin αV inhibitors Cilengitide or SB273005 developed dramatically expansive ascending TAA, accompanied by exacerbated disorganization or loss of elastic fibers. Bulk RNA sequencing results further indicated that the treatment with integrin αV inhibitors exacerbates the pro-inflammatory response in mouse TAA development. These data suggest that integrin αV may be a novel target for TAA intervention. However, it also raises concerns about exposure to integrin αV inhibitors, which are conducted in serious cancer clinical trials, may pose a potential risk of developing aortic aneurysm (AA)/AD.
2025-11-23 | GSE263304 | GEO
Project description:Thoracic aortic aneurysm (TAA) is a perilous disease that can lead to aortic dissection (AD), the pathophysiological mechanisms of which remain largely elusive. To improve our understanding of the molecular mechanism underlying TAA, we conducted a tandem mass tag (TMT)-based proteomics analysis and identified two down-regulated proteins, integrin αV, and integrin αL, in serum samples from patients with type A aortic dissection. We confirmed that integrin αV is extensively expressed in the aortic media, and its expression decreases after dissection, whereas the expression of integrin αL showed no significant alteration. Subsequently, by employing a mouse model of TAA induced by β-Aminopropionitrile (BAPN), we discovered that the mice treated with integrin αV inhibitors Cilengitide or SB273005 developed dramatically expansive ascending TAA, accompanied by exacerbated disorganization or loss of elastic fibers. Bulk RNA sequencing results further indicated that the treatment with integrin αV inhibitors exacerbates the pro-inflammatory response in mouse TAA development. These data suggest that integrin αV may be a novel target for TAA intervention. However, it also raises concerns about exposure to integrin αV inhibitors, which are conducted in serious cancer clinical trials, may pose a potential risk of developing aortic aneurysm (AA)/AD.
2025-11-23 | GSE280456 | GEO
Project description:This study aimed to establish a chronic proximal thoracic aortic aneurysm(cPTAA) model by combining periaortic elastase application and 90-day oral 3-aminopropionitrile fumarate salt(BAPN) administration.Transcriptome Sequencing was performed using Illumina Novaseq platform in 7 murine cPTAAs or 5 sham-operated proximal thoracic aortas.The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed the differentially expressed genes were most enriched in immune and inflammation related pathways.
2024-12-01 | GSE275166 | GEO
Project description:Background: Aortic aneurysm and dissection (AAD) is a fatal vascular emergency with limited mechanism-based therapies. The mitochondrial AAA⁺ ATPase ATAD3A, enriched at organelle contact sites, has been implicated in mitochondrial signaling, but its role in AAD remains unclear. Methods: AAD was induced in wild-type, ATAD3A knock-in (ATAD3A-KI), and vascular smooth muscle cell (VSMC)-specific knockdown (sh-ATAD3A) mice by 3-week β-aminopropionitrile monofumarate (BAPN) intake or 28-day angiotensin II (AngII) infusion via osmotic minipumps. Aortic dilatation, dissection incidence, rupture-related mortality, and histology were assessed. VSMCs were stimulated with AngII in vitro. Mitochondrial function was evaluated using Seahorse bioenergetics, membrane potential assay, and Ca²⁺ imaging. ATAD3A-dihydrolipoamide s-succinyltransferase (DLST) interaction was examined by co-immunoprecipitation. Pharmacological modulation was performed with the copper chelator tetrathiomolybdate (TTM) and the lipoylation inhibitor Devimistat. Results: ATAD3A expression was upregulated in human thoracic aortic dissection samples and in BAPN-treated mouse aortas, with early downregulation then late upregulation in VSMCs. Systemic ATAD3A overexpression mitigated BAPN- and AngII-induced aortic dilatation, reduced dilation incidence, and improved survival, whereas VSMC-specific knockdown accelerated vascular pathology. Mechanistically, ATAD3A overexpression reduced mitochondria-lysosome contacts, limited mitochondrial Ca²⁺ influx, and suppressed the FDXR/FDX1/LIAS lipoylation pathway, decreasing DLST lipoylation and restraining cuproptosis, thereby preserving VSMC viability and delaying AAD progression. Pharmacological inhibition of cuproptosis using TTM or Devimistat attenuated disease severity in vivo. Conclusions: ATAD3A protects against AAD by coordinating organelle contact and metabolic signaling to restrain mitochondrial Ca²⁺ influx, NADPH flux, and DLST lipoylation-dependent cuproptosis in VSMCs. Targeting the ATAD3A-DLST-cuproptosis axis offers mechanistic insight and therapeutic potential for AAD.
2026-06-20 | GSE329337 | GEO
Project description:Adverse aortic remodeling increases the risk of aorta-related adverse events (AAEs) after thoracic endovascular aortic repair (TEVAR) and affects the overall prognosis of aortic dissection (AD). It is imperative to delve into the exploration of prognostic indicators to We performed single-cell transcriptomic and proteomic profiling of aortic lesions and peripheral blood samples, respectively, from patients with AD and healthy subjects. We then integrated single-cell RNA to identify phenotype-relevant subpopulations.
2024-11-01 | GSE254132 | GEO
Project description:Role of Pdk4 in BAPN-induecd aortic dissection in mouse models
| PRJNA1392438 | ENA
Project description:Rationale— Aortic dissection (AD) is a fatal disease that occurs suddenly without preceding clinical signs or symptoms. It is desirable to prevent AD before the onset. Although high salt intake is an established risk factor for cardiovascular diseases, the relationship between high salt intake and AD has not been clarified. Although recent studies have shown that high salt intake promotes interleukin (IL)-17-dependent inflammation, it is unknown whether this mechanism is involved in the pathogenesis of AD. Objective— The purpose of this study was to investigate the effect of high salt challenge on AD and involvement of IL-17. Methods and Results— We used a mouse AD model that was induced by continuous infusion of -aminopropionitrile and angiotensin II. High salt challenge exacerbated AD lesion length compared to the mice without high salt challenge, which was abolished in IL-17 knockout mice. Unexpectedly, deletion of IL-17 resulted in the activation of Smad pathway, induction of synthetic phenotype of smooth muscle cells, remodeling of extracellular matrix in aortic tunica media, reduced stiffness of aortic walls, and less stress-induced activation of NFkB. Conclusions— These findings establish the worsening effect of high salt intake on AD that involves IL-17 pathway through the extracellular matrix metabolism. Salt restriction may represent a low-cost and practical way to reduce AD risk.
2018-12-31 | GSE116434 | GEO
Project description:Colchicine is an alkaloid found in the plant Colchicum, which is currently used for the treatment of acute gout and familial Mediterranean fever, and is being considered for the treatment of a variety of cardiovascular diseases such as pericarditis, atrial fibrillation, and coronary syndromes due to its significant anti-inflammatory effects. Aortic dissection is a cardiovascular disease characterised by a tear in the intima and congestion of the vessel wall leading to vessel wall delamination, with a rapid onset and high lethality. This study investigated the role of colchicine in BAPN-induced aortic dissection in mice. Gavage administration of colchicine along with BAPN modelling for three weeks showed a significant decrease in morbidity and mortality, indicating that colchicine can inhibit the occurrence of aortic dissection in mice.
2024-10-25 | GSE279545 | GEO