Liu Xiu, Zhao Li, Liu Deshen, Zhao Lingna, Tuo Yonghua, Peng Qinbao, Huang Fangze, Song Zhengkun, Niu Chuanjie, He Xiaoxia, Xu Yu, Wan Jun, Zhu Peng, Jian Zhengyang, Guo Jiawei, Liu Yingying, Lu Jun, Liang Sijia, Zheng Shaoyi
Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Department of Neurosurgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
Acta Pharm Sin B. 2025 Jul;15(7):3663-3684. doi: 10.1016/j.apsb.2025.05.016. Epub 2025 May 21.
This study investigated the role of the nuclear factor of activated T cells c3 (NFATc3) in vascular smooth muscle cells (VSMCs) during aortic aneurysm and dissection (AAD) progression and the underlying molecular mechanisms. Cytoplasmic and nuclear NFATc3 levels were elevated in human and mouse AAD. VSMC-NFATc3 deletion reduced thoracic AAD (TAAD) and abdominal aortic aneurysm (AAA) progression in mice, contrary to VSMC-NFATc3 overexpression. VSMC-NFATc3 deletion reduced extracellular matrix (ECM) degradation and maintained the VSMC contractile phenotype. Nuclear NFATc3 targeted and transcriptionally upregulated matrix metalloproteinase 9 (MMP9) and MMP2, promoting ECM degradation and AAD development. NFATc3 promoted VSMC phenotypic switching by binding to eukaryotic elongation factor 2 (eEF2) and inhibiting its phosphorylation in the VSMC cytoplasm. Restoring eEF2 reversed 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. VSMC-NFATc3 promoted VSMC switch and ECM degradation while exacerbating AAD development, making it a novel potential therapeutic target for preventing and treating AAD.
本研究调查了活化T细胞核因子c3（NFATc3）在主动脉瘤和主动脉夹层（AAD）进展过程中在血管平滑肌细胞（VSMC）中的作用及其潜在分子机制。在人和小鼠的AAD中，细胞质和细胞核中的NFATc3水平均升高。与VSMC-NFATc3过表达相反，VSMC-NFATc3缺失可减少小鼠胸主动脉瘤（TAAD）和腹主动脉瘤（AAA）的进展。VSMC-NFATc3缺失可减少细胞外基质（ECM）降解并维持VSMC收缩表型。细胞核NFATc3靶向并转录上调基质金属蛋白酶9（MMP9）和MMP2，促进ECM降解和AAD发展。NFATc3通过与真核生物延伸因子2（eEF2）结合并抑制其在VSMC细胞质中的磷酸化来促进VSMC表型转换。恢复eEF2可逆转VSMC特异性NFATc3基因敲除小鼠中的有益作用。卡巴米喹靶向eEF2并抑制蛋白质合成，可抑制VSMC-NFATc3过表达小鼠的AAD发展和进展。VSMC-NFATc3促进VSMC转换和ECM降解，同时加剧AAD发展，使其成为预防和治疗AAD的新型潜在治疗靶点。
