1 research outputs found
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