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RNA-seq analysis of macrophage NFATc3 or ASK1 effects on metabolic dysfunction-associated steatohepatitis

ABSTRACT: To explore the roles of macrophage NFATc3 and ASK1 in metabolic dysfunction-associated steatohepatitis, we generated macrophage-specific Nfatc3 knockout mice (Nfatc3-MKO), macrophage-specific Ask1 knockout mice (Ask1-MKO),macrophage-specific double knockout (MDKO) mice, macrophage-specific Nfatc3 knockin mice (Nfatc3-MKI), and macrophage-specific Ask1 knockin mice (Ask1-MKI). Lyz2-Cre mice were used as control. Eight-week-old male Lyz2-Cre, Nfatc3-MKO, Ask1-MKO, and MDKO mice were treated with methionine- and choline-deficient (MCD) diet for 4 weeks. Subsequently, mouse liver tissues were isolated and subjected to RNA sequencing analysis. In addition, mouse bone marrow-derived macrophages (BMDMs) were isolated from Lyz2-Cre, Nfatc3-MKI, and Ask1-MKI mice and were also subjected to RNA sequencing analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE314637 | GEO | 2026/01/20

REPOSITORIES: GEO

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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.

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RNA-seq analysis of macrophage NFATc3 or ASK1 effects on metabolic dysfunction-associated steatohepatitis

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