Abstract 3016: Cytoplasmic And Nuclear Nfatc3 Cooperatively Contributes To Vascular Smooth Muscle Cell Dysfunction And Drives Aortic Aneurysm And Dissection

Background: Aortic aneurysm and aortic dissection (AAD) are fatal diseases resulting in catastrophic aortic rupture and sudden death. The degradation of the extracellular matrix (ECM) and the phenotypic transformation of vascular smooth muscle cells (VSMCs) are crucial pathological mechanisms in AAD. We previously found that macrophage NFATc3 inhibits atherosclerosis and foam cell formation. However, the precise role of VSMC-NFATc3 in AAD remains unknown. Aims: This study investigates the role of NFATc3 in VSMCs in AAD progression and the molecular mechanisms. Methods: To investigate the role of NFATc3 in VSMCs in AAD, we used VSMC-NFATc3-specific knockout and knock-in mice. By establishing mouse models for thoracic AAD (TAAD) and abdominal aortic aneurysm (AAA), we employed techniques such as RNA sequencing, mass spectrometry, and chromatin immunoprecipitation to study the mechanistic role of VSMC-NFATc3 in AAD. Results: Cytoplasmic and nuclear NFATc3 levels are elevated in human and mouse AAD. VSMC-NFATc3 deletion reduces TAAD and AAA progression in mice, contrary to VSMC-NFATc3 overexpression. VSMC-NFATc3 deletion reduces ECM degradation and maintains the VSMC contractile phenotype. Nuclear NFATc3 targets and transcriptionally upregulates MMP9 and MMP2, promoting ECM degradation and AAD development. NFATc3 promotes VSMC phenotypic switching by binding to eukaryotic elongation factor 2 (eEF2) and inhibiting its phosphorylation in the VSMC cytoplasm. Restoring eEF2 reverses the beneficial effects in VSMC-specific NFATc3-knockout mice. Cabamiquine—targets eEF2 and inhibits protein synthesis—inhibited AAD development and progression in VSMC-NFATc3-overexpressing mice. Conclusion: VSMC-NFATc3 promotes VSMC switch and ECM degradation while exacerbating AAD development, making it a novel potential therapeutic target for preventing and treating AAD.