Identification of a Novel Hybridization from Isosorbide 5‑Mononitrate and Bardoxolone Methyl with Dual Activities of Pulmonary Vasodilation and Vascular Remodeling Inhibition on Pulmonary Arterial Hypertension Rats

Given the clinical therapeutic efficacy of oral-dosed bardoxolone methyl (<b>1</b>) and the selective vasodilatory effect caused by inhalation of nitric oxide (NO) on pulmonary arterial hypertension (PAH) patients, a new hybrid (CDDO-NO, <b>2</b>) from <b>1</b> and NO donor isosorbide 5-mononitrate (<b>3</b>) was designed and synthesized. This hybrid could liberate <b>1</b> and NO in the lungs of rats after trachea injection. Significantly, <b>2</b> lowered mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure <b>(</b>RVSP), decreased right ventricular hypertrophy (RVH), and attenuated pulmonary artery medial thickness (PAMT) and vascular muscularization in monocrotaline (MCT)-induced PAH rats. Meanwhile, <b>2</b> inhibited overproliferation of perivascular cells and diminished macrophage infiltration and oxidative stress by inactivation of NOX4. In addition, <b>2</b> markedly reduced cardiac hypertrophy and fibrosis in the PAH rats. Overall, <b>2</b> exhibited potent dual activities of pulmonary vasodilation and vascular remodeling inhibition, suggesting that it may be a promising agent for PAH intervention