Contribution of reactive oxygen species via the OXR1 signaling pathway in the pathogenesis of monocrotaline-induced pulmonary arterial hypertension: The protective role of Crocin

Abstract

Aim

Pulmonary arterial hypertension (PAH) identified by progressive increase in pulmonary vascular resistance and pressure, ultimately leading to right ventricular failure and sudden death. Oxidation resistance 1 (OXR1) and its downstream target genes has a pivotal role for defense against oxidative stress. But its molecular function is unknown in respiratory system disorders. This study designed to determine whether PAH associated with oxidative stress and OXR1 signaling pathway modulation. Also, Crocin co-treatment evaluated to determine the possible role and mechanism in pulmonary arterial hypertension.

Main method

The PAH model was induced by a single dose of MCT. It was given intraperitoneal administration of Crocin or saline for 21 consecutive days the other groups in this study. In the last day of experiment, hemodynamic parameter and right ventricular hypertrophy was evaluated as PAH index. The expression levels of OXR1, P21 and Nrf2 genes were detected through RT-PCR. Moreover, oxidative stress index and antioxidant capacity were measured and histological examination were used to determine the lung tissue injuries.

Key findings

Results of the current study demonstrated that the OXR1 and P21 gene expression significantly decrease in PAH which is associated with increase of lipid peroxidation and decrease antioxidant capacity in lung tissue. Crocin co-treatment significantly improved the hemodynamic, oxidative stress biomarkers and histological data of the PAH rats, which associated with increase of OXR1 and its downstream target genes.

Significance

This report reveals the critical role of OXR1 in pathogenesis of oxidative stress-related pulmonary disease. Current experiment also provides evidence that Crocin has a protective effect against MCT-induced pulmonary arterial hypertension by modulation of OXR1 signaling pathway in rats.

Introduction

Pulmonary arterial hypertension (PAH) is a syndrome that characterized by a range of pathological changes in pulmonary artery including increase in pressure and vasoconstriction, ultimately leading to chronic right ventricle pressure overload, heart failure and sudden death [1]. Despite the destructive effects of this disease, molecular mechanisms of PAH is not clearly understood. Recent evidence obtained from human and animal studies documented that oxidative stress plays a pivotal role in the pathogenesis of PAH [2,3]. Oxidative stress occurs with increased production of reactive oxygen (ROS) and nitrogen species (RNS) and insufficient normal function of antioxidant system which can lead to mitochondrial dysfunction and cell death. Numerous studies reveal that various types of proteins are localized to the cell nucleus to counteract the several damaging effects of ROS, including superoxide dismutase, glutathione and catalase [4]. The oxidation resistance 1 (OXR1) act as an essential sensor of cellular oxidative stress which present in many eukaryotic organisms including humans. Modulation of OXR1is believed to involve in regulation of the genes related to antioxidant defense system required to reactive oxygen species detoxification by upregulation of its target genes [[5], [6], [7]]. In this context, one study has identified that OXR1 as a novel gene can suppress oxidative stress by stimulating upregulation of P21 and nuclear factor erythrocyte 2 related factor 2 (Nrf2) and significant crosstalk is observed in mammalian antioxidant and inflammatory systems. It has been suggested that the OXR1-P21-Nrf2 antioxidant defense system acts to decrease various pathological changes induced by oxidative stress [5]. Also, the P21 protective molecular mechanism against reactive oxygen species-induced cell injuries through upregulation of the Nrf2-dependent antioxidant response has been documented in the previous study [8]. To date, there is not any document about OXR1 signaling pathway function in respiratory system disorders.

Crocus sativus L. known as the Saffron is a flower belonging to the Iridaceae family and commonly found in Southwest Asia [9]. Crocin is a carotenoid ingredient which is the main active pharmacologically component of Crocus sativus L. and have shown promising antioxidant properties [10]. Chemical studies have identified pharmacological effects of Crocin including anti-atherosclerotic, antioxidant, free radical scavenging, anti-inflammatory and anticancer [[11], [12], [13]]. Moreover, previous studies documented the cardioprotective properties and pulmonary protective effect of Crocin against oxidative stress induced injuries which mediated by activation of Nrf2 signaling pathway [[14], [15], [16]]. Current experiment used a rat model of PAH to show whether level of OXR1 has a critical role for survival rate and severity of lung injuries induced by oxidative stress in response to PAH. Furthermore, this report provides evidence that Crocin as a natural antioxidant has a potential role against MCT-induced pulmonary arterial hypertension by modulation of OXR1 signaling pathway in rats.