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