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Transcriptomic analysis of mouse aortas from NFATc3 flox mice and VSMC-specific NFATc3 knockout mice with BAPN treatment

ABSTRACT: Transcriptomic analysis of mouse aortas from NFATc3 flox mice and VSMC-specific NFATc3 knockout mice with BAPN treatment

PROVIDER: PRJNA981105 | ENA |

REPOSITORIES: ENA

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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.

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.

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Transcriptomic analysis of mouse aortas from NFATc3 flox mice and VSMC-specific NFATc3 knockout mice with BAPN treatment

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