Downregulation of PCAF inhibits vascular smooth muscle cells senescence by reducing oxidative stress injury via activating the Nrf2/ARE pathway

Vascular aging represents the common pathological basis of aging-related diseases, with vascular smooth muscle cells (VSMCs) senescence playing a pivotal role. P300/CBP-associated factor (PCAF), a transcriptional coactivator linked to diverse physiological processes, has an undefined role in VSMCs aging. This study investigated PCAF's function in VSMC senescence and its underlying mechanisms. Using siRNA adenovirus to downregulate PCAF and angiotensin II (AngII) to induce senescence, we assessed β-galactosidase activity, senescence-associated secretory phenotypes (SASP), and cell cycle proteins (p53, p21, p16). Transcriptomic analysis revealed PCAF's association with oxidative stress and the Nrf2-ARE pathway. Results demonstrated that PCAF downregulation significantly attenuated VSMCs senescence and AngII-induced oxidative stress by enhancing Nrf2-ARE pathway activity. Crucially, Nrf2 silencing reversed these protective effects. In conclusion, PCAF inhibition mitigates VSMCs senescence via Nrf2-ARE-mediated antioxidant activation, identifying PCAF as a promising therapeutic target for vascular aging.