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.

Magnesium Lithospermate B Derived from Salvia miltiorrhiza Ameliorates Right Ventricle Remodeling in Pulmonary Hypertensive Rats via Inhibition of NOX/VPO1 Pathway

“…Interestingly, some natural compounds exert therapeutic effect on PAH via targeting NOX. For example, a number of studies have reported that resveratrol was able to prevent the development of PAH through a mechanism involving a suppression of NOX [6]. As an active ingredient of S. miltiorrhiza, MLB attracts our special attention because its antioxidative effect is greater than that of α-lipoic acid, a super antioxidant.…”

“…In the process of PAH development, the RV adapts to the elevated pulmonary artery pressure by increasing its wall thickness and contractility. Besides the pressure overload, multiple factors including neurohumoral activation [5], oxidative stress [6], and inflammation [7] actually contribute a lot to the pathophysiology of RV remodeling in PAH. Among them, oxidative stress attracts intensive attention recently.…”

“…There is growing evidence that NOX is activated in animals or humans with PAH, indicating that NOX-derived ROS may contribute to the development of PAH [15][16][17]. Furthermore, our previous studies have demonstrated that NOX coordinates with vascular peroxidase 1 (VPO1) to amplify the role of NOX-derived ROS in mediation of oxidative injury in myocardial ischemia/reperfusion injury and vascular remodeling in PAH [6,18] because VPO1 can catalyze NOX-derived hydrogen peroxide (H 2 O 2 ) to produce more powerful oxidant hypochlorous acid (HOCl). Based on these reports, we postulated that targeting NOX/VPO1 pathway might be a valuable strategy for the prevention of RV remodeling in PAH.…”

Resveratrol prevents cadmium activation of Erk1/2 and JNK pathways from neuronal cell death via protein phosphatases 2A and 5

“…), and in hypoxia‐induced rat model of pulmonary arterial hypertension (Liu et al . ). Our group has demonstrated that Cd activates JNK, Erk1/2, and p38 pathways via induction of ROS (Chen et al .…”

Resveratrol and SIRT1 Activators for the Treatment of Aging and Age-Related Diseases

“…Moreover, to improve oral bioavailability of RSV-specific complexes with liposomes, lipid or synthetic nanoparticles have been made, even if they resulted with low therapeutic potential [79,80]. In respiratory diseases reproduced in rodent like pulmonary hypertension, RSV ameliorates asthma and fibrosis via SIRT1 activation [81,82] and also its derivative, trimethoxystilbene, demonstrated antioxidant and anti-inflammatory properties in rats exposed to hypoxia [83]. Recently, Bastin and Djouadi [84] reviewed RSV potentiality against mitochondrial damage and myopathies, and promising results in an animal model of a fatal genetic disease called Duchenne muscular dystrophy were reported.…”