BACKGROUND The aim of this study was to investigate the potential beneficial effects of celastrol, a compound with anti-inflammatory and antioxidant properties, on vascular smooth muscle cells (VSMCs) under hypertensive conditions. METHODS Hypertension was induced in rats by fructose feeding. Hypertensive rats were injected with celastrol, and systolic and diastolic blood pressure were monitored by the tail-cuff method. Insulin sensitivity in animals was measured by GTT. Serum levels of inflammatory cytokines were determined by ELISA. Real-time RT-PCR and Western blot were applied to quantify mRNA and protein levels in tissues and primary cultured VSMCs. Generation of reactive oxygen species (ROS) was measured using lucigenin chemiluminescence for tissue homogenates and DCF-DA staining for VSMC cells. RESULTS Celastrol decreased both systolic and diastolic blood pressure while improving insulin sensitivity in fructose-induced hypertensive rats. Celastrol also inhibited vascular and cardiac hypertrophy. Hypertension augmented circulating and mRNA levels of inflammatory cytokines, and celastrol treatment suppressed their induction. Celastrol also blocked activation of ERK/MAPK and Akt signaling both in vivo and in vitro. More importantly, celastrol increased heme oxygenase-1 (HO-1) expression and activity, whereas zinc protoporphyrin 9 (ZnPP9), a HO-1 inhibitor, partially abolished the beneficial effects of celastrol on hypertensive rats and VSMCs. Finally, ROS generation in tissue homogenates and in VSMCs was reduced by celastrol. CONCLUSIONS These findings suggest that celastrol attenuates hypertension-induced inflammation and oxidative stress in VSMCs via HO-1 induction, and this compound may therefore serve as a novel drug to treat hypertension.