[Abstract] Objective: To investigate the effects of a novel hybrid compound CDDO-NO from bardoxolone methyl (CDDO-Me) and NO donor isosorbide 5-mononitrate on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. Methods: Male Sprague-Dawley rats were randomly divided into 6 groups: control (Con) group, MCT group, MCT + 10μg/kg CDDO-NO (MCT+10NO) group, MCT + 30μg/kg CDDO-NO (MCT+30NO) group, MCT + 7μg/kg CDDO-Me (MCT+7Me) group and MCT + 21μg/kg CDDO-Me (MCT+21Me) group. PAH in rat was induced by a single dose injection of 60mg/kg MCT intraperitoneally, the rats in treated groups were placed in an inExpose system for daily aerosol CDDO-NO or CDDO-Me inhalation for 28 days. Right ventricular systolic pressure (RVSP) by right heart catheter, and right ventricular hypertrophy index (RVHI) as well as RV-to-body weight ratio (RV/BW) were measured. Hematoxylin-eosin (HE) staining was used to detect the pulmonary artery medial thickness (PAMT) and the morphological changes of the right ventricle, α-smooth muscle actin (α-SMA) immunohistochemistry was used to investigate the muscularization of distal vessels. Masson’s trichrome staining (MTS) was performed to evaluate the fibrosis of arterioles. Results: Right heart catheter and right ventricular remodeling indicators showed that inhalation of either CDDO-NO or CDDO-Me suppressed elevations of RVSP, RVHI and RV/BW induced by MCT in PAH rats. 30μg/kg CDDO-NO showed stronger inhibitory effect in RVHI and RV/BW than that of the equal dose of parent compound CDDO-Me (21μg/kg). Moreover, pathological studies indicated that 30μg/kg CDDO-NO had better effects in alleviating right ventricular myocardial hypertrophy and PAMT, and reducing the proportion of fully muscularized vessels and the area of collagen deposition than those of CDDO-Me (21μg/kg). Conclusion: Inhalation of CDDO-NO can ameliorate MCT-induced PAH in rats by inhibiting pulmonary vascular remodeling, and the effect of CDDO-NO is superior to parent compound CDDO-Me. These results suggest that CDDO-NO could be a promising drug for the treatment of PAH.