Mechanisms of N-acetylcysteine in reducing monocrotaline-induced pulmonary hypertension in rats: Inhibiting the expression of Nox1 in pulmonary vascular smooth muscle cells

Abstract

The aim of the present study was to investigate the impact of N‑acetylcysteine (NAC) on the expression of reduced nicotinamide adenine dinucleotide phosphate oxidase 1 (Nox1), and the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) in rats exhibiting monocrotaline (MCT)‑induced pulmonary hypertension, and to investigate the possible mechanisms and treatment roles of NAC in pulmonary vascular remodeling (PVR). A total of 18 Wistar rats were randomly divided into three groups: The control (C) group; the MCT (M) group; and the NAC (N) group. The right ventricular hypertrophy index (RVHI) and other indicators were recorded 6 weeks subsequently. Groups C and M were divided into two subgroups: Groups C1 and M1 (control); and group C2 and M2 group (treated with ML171). Group N was not sub‑divided. PASMCs were isolated, and the vascular remodeling and Nox1 positioning were observed. The expression of Nox mRNA in each group, and the proliferation, apoptosis, and superoxide dismutase (SOD) activity of PASMCs, prior to and following the ML171 treatment, were measured. NAC was able to decrease RVHI and other indicators (P<0.001). The mRNA expression of Nox1 and Nox4 in group M was significantly increased compared with group C (P<0.05), and NAC was able to significantly decrease the expression of these two factors in lung tissue (P<0.001). MCT‑PASMCs exhibited differences in Nox1 mRNA expression (P<0.001), and the total SOD activity was Nox1‑dependently increased (r=0.949; P<0.001). NAC was able to decrease Nox1‑derived reactive oxygen species in PASMCs, thereby improving PVR. Nox1 was able to increase SOD activity, thereby demonstrating its positive effect on the proliferation of MCT‑PASMCs.

Sex Dimorphism in Pulmonary Hypertension: The Role of the Sex Chromosomes

“…NOX1 activity promoted Grem1 upregulation by activating the transcription factor CREB. It has been previously shown that CREB is selectively activated by hypoxia in the mouse lung in vivo and is also activated in the Sugen-hypoxia model of PAH in rats [ 69 , 70 , 115 ].…”

“…When NOX1 expression and activity in monocrotaline-induced pulmonary hypertension in rats was inhibited, pulmonary vascular resistance was reduced and pulmonary hypertension attenuated [ 69 ]. Furthermore, hypoxia-induced pulmonary hypertension was attenuated in female NOX1 −/− deficient mice [ 72 ].…”

Vasoconstrictor Mechanisms in Chronic Hypoxia-Induced Pulmonary Hypertension: Role of Oxidant Signaling

“…NOX1 expression is greater in PAs from PAH patients compared to vessels from control patients [ 83 ] and contributes to the proliferation of both PAEC [ 83 ] and PASMC [ 86 ]. In monocrotaline-induced PAH model, NOX1 expression is increased in PASMCs [ 87 ].…”

“…In monocrotaline-induced PAH model, NOX1 expression is increased in PASMCs [ 87 ]. Moreover, N-acetylcysteine, which suppresses NOX1 expression, is protective against monocrotaline-induced PAH [ 86 ]. In addition to PAH, NOX1 has also been shown to participate in PH elicited by CH as evidence by effects of genetic global deletion of NOX1 to abolish the CH-induced elevation in right ventricular systolic pressure (RVSP), right ventricle (RV) hypertrophy and PA remodeling in mice [ 98 ].…”

Role of Gender in Regulation of Redox Homeostasis in Pulmonary Arterial Hypertension

“…Nevertheless, the pathological role of ROS produced by Nox enzymes in PAH is also well established. Thus, the expression of Nox1 was found to be increased in MCT rat model [89], while antioxidant therapy mediated decrease in Nox1 expression attenuated RV hypertrophy. Elevated Nox1 expression was shown to stimulate pulmonary artery smooth muscle cell proliferation and migration in rat PAH model [90,91].…”