Transcriptomic analysis of mouse aortas from NFATc3 flox mice and VSMC-specific NFATc3 knockout mice with BAPN treatment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE234349 | GEO | 2025/07/30
REPOSITORIES: GEO
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Project description:Transcriptomic analysis of mouse aortas from NFATc3 flox mice and VSMC-specific NFATc3 knockout mice with BAPN treatment
| PRJNA981105 | ENA
Project description:BACKGROUND: Thoracic aortic dissection (TAD) and abdominal aortic aneurysm (AAA) are fatal cardiovascular diseases with a high mortality rate in rupture events, closely related to vascular smooth muscle cell (VSMC) transformation from contractile to synthetic type and extracellular matrix degradation. NFATc3 in macrophages has recently been revealed as an atherosclerosis and foam cell formation negative regulator. However, the role of NFATc3 in aortic aneurysm and dissection (AAD) remains unknown. Therefore, we aimed to investigate the role of VSMC in NFATc3 in developing AAD and establishing NFATc3 as a novel target to treat AAD. METHODS: NFATc3 expression was measured in human and mouse aortic dissection and aneurysm samples. To investigate the role of VSMC-NFATc3 in AAD, we generated VSMC-specific NFATc3 knockout and knockin mice from three different murine AAD models, including proprotein convertase subtilisin/kexin type 9/ AngII (angiotensin II), β-aminopropionitrile (BAPN)/AngII models and BAPN models. The molecular mechanisms underlying NFATc3 function were investigated using RNA-seq analysis, mass spectrometry analysis, gelatin zymography, a luciferase reporter assay ChIP-qPCR, nuclear run-on assay, polyribosome profiling, coimmunoprecipitation, and mammalian 2-hybrid assay. RESULTS: We found that cytoplasmic and nuclear NFATc3 levels are elevated in human and mouse aortic dissection aneurysms. VSMC-specific NFATc3 deletion in mice reduced TAD and AAA progression, whereas VSMC-specific NFATc3 overexpression mice exhibited the opposite phenotype. VSMC-NFATc3 aggravated AAD independently of blood pressure regulation. VSMC-specific NFATc3 deletion reduces extracellular matrix degradation and maintains VSMC contractile phenotype. Mechanistically, nuclear NFATc3 specifically targeted and transcriptionally up-regulated MMP9 and MMP2, promoting extracellular matrix degradation and AAD development. We found that NFATc3 promoted VSMC phenotypic switch by binding to eEF2 and inhibiting its phosphorylation in VSMC cytoplasm, increasing protein synthesis and translational elongation, downregulating VSMC differentiation markers, and eventually exacerbating AAD development. We found that cabamiquine, a novel antimalarial agent that targets eEF2 and inhibits protein synthesis, inhibited AAD development and progression in VSMC-specific NFATc3 overexpression mice. Conclusion: Thus, VSMC-NFATc3 promotes VSMC change from contractile to synthetic type and extracellular matrix degradation, exacerbating AAD development, suggesting that VSMC-NFATc3 is a novel therapeutic target for preventing and treating AAD.
2023-06-08 | PXD042816 |
Project description:Myocardin (Myocd) plays an important role in the maintenance and homeostasis of the vasculature. The loss of Myocd results in vascular smooth muscle cell (VSMC) phenotypic transition and thoracic aortic aneurysms and dissections (TAADs) by downregulating VSMC contractile genes. VSMC phenotypic transition plays a key role in the formation of abdominal aortic aneurysms and dissections (AAADs). However, little is known about the role of Myocd in AAAD. The effect of Myocd on AAA formation was proven in an angiotensin II (Ang II)-induced AAD model. Myocd overexpression or knockdown was achieved by the injection of the corresponding adeno-associated virus serotype 9 (AAV9) through the tail vein. The knockdown of Myocd in C57BL/6J mice treated with angiotensin II promoted the formation of AAAD, as demonstrated by increases in the maximal aortic diameter, vascular inflammation and elastin degradation relative to the control group, while Myocd-overexpressing ApoE-/- mice infused with Ang II were less likely to develop AAAD. Mechanistically, Myocd deficiency significantly repressed VSMC marker gene expression. In addition, qPCR results showed that Myocd knockdown promoted the expression of lncRNAs, which showed increased levels in human AAD tissues. Our results indicated the pivotal role of Myocd in protecting against AAAD formation.
2024-10-25 | GSE180990 | GEO
Project description:To investigate the role of TET2 in osteogenic differentiation of smooth muscle cells (SMCs) in vivo, we performed single cell RNA-seq in cholecalciferol overload-induced calcified aortas of Tet2flox/flox and SMC specific Tet2 knock-out mice (Tet2SMC-KO).
2024-04-16 | GSE263739 | GEO
Project description:Background: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular event characterized by high mortality rates. Previous studies have shown that matrix metalloproteinases 19 (MMP19) was involved in TAAD formation, while the detailed role of MMP19 in TAAD pathogenesis and underlying mechanism remain unclear. Methods: To investigate the role of MMP19 in the progression of TAAD, we generated global Mmp19 knockout mice, as well as VSMCs (vascular smooth muscle cells)-specific Mmp19 knockdown mice, and established a BAPN-induced TAAD model. To elucidate the signaling pathways modulated by Aggrecan, we employed an adeno-associated virus serotype 9 (AAV9) vector encoding Acan short hairpin RNA (shRNA) for VSMC-specific knockdown of Acan. Ultimately, we injected an AAV vector encoding VSMC-specific Mmp19 into BAPN-induced TAAD mice to assess whether MMP19 can mitigate the development of TAAD. Results: Our findings revealed elevated mRNA and protein levels of MMP19 in the aortas of both TAAD mice and patients. The systemic ablation of Mmp19, as well as VSMC-specific Mmp19 knockdown, significantly exacerbated BAPN-induced progressive TAAD, and TAAD-related cardiovascular remodeling. Mmp19 deficiency resulted in the accumulation of Acan, but not Vcan, within the aorta, driving the phenotypic switch of VSMCs from contractile to synthetic state through activting Wnt/β-catenin signaling pathway. The selective inhibitor of Wnt/β-catenin signaling, MASB, was effective in reversing the dedifferentiation of VSMCs induced by aggrecan accumulation. Notably, the specific knockdown of Acan in VSMCs restored the contractile phenotype of VSMCs and inhibited Wnt/β-catenin signaling, thereby alleviating BAPN-induced TAAD in Mmp19-/- mice. Additionally, VSMC-specific complementation of MMP19 also alleviated the progressive TAAD phenotype in Mmp19-/- mice. Conclusions: The study underscores that MMP19 deficiency exacerbates TAAD by promoting Acan aggregation and destroying the homeostasis of VSMCs by activating Wnt/β-catenin signaling pathway. These results posit MMP19 as a promising novel therapeutic target for TAAD intervention.
2025-04-01 | GSE287828 | GEO
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:The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 subjects were recruited for screening of differentially expressed plasma microRNAs. 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. miR-1204 aggravated angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuated β-aminopropionitrile monofumarate-induced AAD formation. Mechanistically, miR-1204 directly targeted myosin light chain kinase (MYLK) to promote VSMCs to acquire senescence-associated secretory phenotype (SASP) and lose their contractile phenotype. Overexpression of MYLK reversed miR-1204-induced VSMC senescence, SASP and contractile phenotype changes, and the decrease of transforming growth factor-β signaling pathway. Our findings suggest aging aggravates AAD via miR-1204-MYLK signaling axis.
2024-04-01 | PXD048658 | Pride
Project description:Atherosclerosis (AS) is one of the most common diseases in middle-age and elderly population. Lipid metabolism disorder induced foaming of vascular smooth muscle cell (VSMC) is an important pathological process of AS. Mitochondria plays an important role in lipids metabolism. While it is not known whether regulating mitochondrial function can protect ox-LDL induced VSMC foaming via metabolic reprogramming. With ox-LDL induced mouse model of VSMC injury, the injury effect of ox-LDL and the protective effect of mdivi-1, the mitochondrial fission inhibitor on mitochondrial morphology and function of VSMC, and the formation of lipid droplet were observed. With metabonomics and proteomics techniques, the main lipid metabolites and regulation proteins were identified. The results showed that Ox-LDL induced a significant mitochondrial fission and fragmentation of VSMC, and mitochondrial function disorder along with lipid deposition and foaming. Mdivi-1 significantly antagonized the damage effect of ox-LDL on mitochondrial morphology and function of VSMC, and blocked the lipid deposition. Metabonomics analysis found 848 different metabolites between ox-LDL and mdivi-1 treatment group, in which the lipid metabolites were the main, and heptadecanoic acid, palmitoleic acid and myristic acid were the critical metabolites changed most. Proteomics results showed that there were 125 differential expressed proteins between ox-LDL and mdivi-1 treatment, acetyl -CoA carboxylase1 and fatty acid synthase were the main differential expressed proteins. This study suggest that Mitochondrial fission plays an important role in VSMC lipid deposition and foaming. Inhibition of mitochondrial fission may effectively fight against ox-LDL induced lipid deposition and foaming of VSMC via improving mitochondrial function and metabolic reprogramming. This finding provides a new insight for prevention and treatment of AS.
2022-10-14 | PXD035671 | Pride
Project description:Analysis of RNAs from VSMCs to find altered pathways in VSMC by CKD
2024-04-08 | GSE229679 | GEO