Inhibition of NOX/VPO1 pathway and inflammatory reaction by trimethoxystilbene in prevention of cardiovascular remodeling in hypoxia-induced pulmonary hypertensive rats.

ABSTRACT

Recent studies show that resveratrol exerts beneficial effects on prevention of pulmonary hypertension. This study is performed to explore the effects of trimethoxystilbene, a novel resveratrol analog, on rat pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-induced pulmonary arterial hypertension (PAH) and the underlying mechanisms. Sprague-Dawley rats were placed in a chamber and exposed to 10% O(2) continuously for 4 weeks to induce PAH. The effects of trimethoxystilbene (5 or 10 mg/kg per day, intragastric [i.g.]) and resveratrol (as a positive control, 25 mg/kg per day, i.g.) on hypoxia-induced PAH vascular remodeling and right ventricle hypertrophy were evaluated. At the end of experiments, the index for pulmonary vascular remodeling and right ventricle hypertrophy, inflammatory cell infiltration in lung tissue, the plasma levels and lung tissue contents of hydrogen peroxide (H(2)O(2)), the mRNA and protein levels for NADPH oxidases (NOX2, NOX4) and vascular peroxidase 1 (VPO1) in pulmonary artery or right ventricle were measured. The results showed that trimethoxystilbene treatment significantly attenuated hypoxia-induced pulmonary vascular remodeling (such as decrease in the ratio of wall thickness to vessel external diameter) and right ventricle hypertrophy (such as decrease in the ratio of right ventricle weight to the length of the tibia), accompanied by downregulation of NOX2, NOX4, and VPO1 expression in pulmonary artery or right ventricle, decrease in H(2)O(2) production and inflammatory cell infiltration in lung tissue. Trimethoxystilbene is able to prevent pulmonary vascular remodeling and right ventricle hypertrophy in hypoxia-induced rat model of PAH, which is related to inhibition of the NOX/VPO1 pathway-mediated oxidative stress and the inflammatory reaction.