Targeting NFAT5 attenuates high sodium-induced vascular aging by re-sensitizing senescent smooth muscle cells to apoptosis

Chronic high sodium intake precipitates vascular aging; however, the molecular signaling remain poorly defined. Nuclear factor of activated T cells 5 (NFAT5) is a central regulator of the cellular osmotic stress response; however, its specific role in modulating vascular senescence signaling remains unknown. Here, we investigated whether NFAT5 signaling mediates high‑sodium-induced vascular aging and evaluated the therapeutic potential of the specific NFAT5 inhibitor KRN5. We utilized C57BL/6 J mice fed a high‑sodium diet and cultured primary vascular smooth muscle cells (VSMCs) under hypertonic conditions to model vascular aging in vivo and in vitro. Mechanistic studies, including RNA Sequencing, chromatin immunoprecipitation, and luciferase reporter assays, were performed to identify NFAT5 transcriptional targets. We found high sodium accelerated vascular aging and VSMC senescence, accompanied by a marked upregulation and nuclear activation of NFAT5. KRN5 significantly attenuated these aging phenotypes and suppressed the senescence-associated secretory phenotype (SASP) in vivo. Mechanistically, activated NFAT5 conferred robust Apoptosis resistance to senescent VSMCs by shifting the Bcl-2 Family balance towards cell survival. Specifically, NFAT5 directly binds to a conserved region of the Bcl-xL promoter to drive its transcription. Consequently, KRN5 effectively re-sensitizing senescent VSMCs to Apoptosis. Collectively, our findings identify the NFAT5 signaling pathway as a critical mechanistic link between high sodium intake and vascular aging. KRN5 is a novel senolytic strategy that dismantles the Bcl-XL-dependent survival mechanism in senescent VSMCs.