Betulinic Acid Attenuates Vascular Smooth Muscle Cell Senescence and Aortic Vascular Aging via PPAR-α/CPT1A-Mediated Fatty Acid Oxidation

Vascular stiffness and aging are critical contributors to cardiovascular diseases. Whether betulinic acid (BA), a natural triterpenoid, alleviates vascular aging remains unclear. Mouse aortic smooth muscle cells (MASMCs) with oleic acid (OA)-induced lipotoxic senescence were treated with BA (30 μM). Transcriptomic analysis and functional assays were conducted. <i>In vivo</i>, ApoE^-/- mice fed a high-fat diet received oral BA (25 mg/kg/day) for 14 weeks. OA-induced lipotoxic senescence was associated with overactivation of peroxisome proliferator-activated receptor alpha (PPAR-α)/fatty acid oxidation (FAO) signaling, which was attenuated by BA intervention. Molecular docking suggested that BA binds to the Arg226 site of PPAR-α, which was further supported by surface plasmon resonance analysis. BA significantly reduced OA-induced expression of P16, P21, and P53 (<i>p</i> < 0.05), inhibited reactive oxygen species generation, and improved mitochondrial function, indicating pronounced antisenescence effects of BA. Moreover, PPAR-α overexpression reversed these protective effects. In ApoE^-/- mice, BA intervention reduced vascular pulse wave velocity (2.7 ± 0.32 <i>vs.</i> 3.3 ± 0.45 m/s, <i>p</i> < 0.05) and intima-media thickness (0.114 ± 0.012 <i>vs.</i> 0.137 ± 0.018 mm, <i>p</i> < 0.05). BA attenuates MASMC lipotoxic senescence and aortic metabolism-associated vascular aging by inhibiting PPAR-α/carnitine palmitoyl transferase 1A-mediated FAO, suggesting a potential metabolic-targeted strategy for preventing lipid-associated vascular aging.