Naringin Reverses High-Cholesterol Diet-Induced Vascular Dysfunction and Oxidative Stress in Rats via Regulating LOX-1 and NADPH Oxidase Subunit Expression.

Sirinat Pengnet,Wachirawadee Malakul,Phinsuda Sumarithum,Sakdina Prommaouan

doi:10.1155/2019/3708497

Abstract

Hypercholesterolaemia is associated with oxidative stress and endothelial dysfunction and leads to the development of atherosclerosis. Naringin exhibits cardiovascular protective and antioxidant properties. Therefore, the aim of this study was to assess the effect of naringin administration on vascular oxidative stress and endothelial dysfunction in hypercholesterolaemic rats and to elucidate its underlying mechanism. Sprague Dawley rats were fed a diet with 1.5% cholesterol (HCD) for 8 weeks to induce hypercholesterolaemia. Naringin (100 mg/kg body weight) was orally administrated to rats during the last 4 weeks of the diet treatment. After 8 weeks, the thoracic aorta was isolated to determine vascular function and nitric oxide (NO) levels. The aortic superoxide anion (O2−) level was detected using dihydroethidium (DHE) fluorescence staining. Protein expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, and inducible nitric oxide synthase (iNOS), as well as oxidative damage markers, was also evaluated in aortae. Naringin treatment of hypercholesterolaemic rats enhanced aortic NO levels, restored endothelium-dependent responses to acetylcholine (ACh), and reduced aortic O2− levels. Furthermore, naringin treatment decreased LOX-1, NADPH oxidase subunits (p47phox, Nox2, and Nox4), and iNOS as well as oxidative damage markers (3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE)) expression in aortic tissues from hypercholesterolaemic rats. These results demonstrate that naringin treatment improves endothelium dysfunction in hypercholesterolaemic rats, at least partially by decreasing oxidative stress via downregulation of LOX-1 and NADPH oxidase.

Highlights

Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality worldwide [1]
Feeding the rats with a high-cholesterol diet (HCD) for 8 weeks caused a significant increase in total cholesterol (TC), TG, and Low-density lipoprotein cholesterol (LDL-C) and a decrease in high-density lipoprotein cholesterol (HDL-C) compared with control rats
Our results show that the treatment of hypercholesterolaemic rats with naringin for 4 weeks restores endothelium-dependent relaxation and nitric oxide (NO) levels in aortae

Summary

Introduction

Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality worldwide [1]. Hypercholesterolaemia has been shown to be a major risk factor for atherosclerosis, associated with increasing oxidative stress and impaired endothelial function [2, 3]. Dysregulation of endothelial function is thought to be one of the earliest manifestations of atherosclerosis and is characterized by reduced endothelium-dependent vasodilation, which is mainly mediated by NO [5]. Accumulating evidence has shown that reactive oxygen species (ROS) generated during hypercholesterolaemia are involved in key processes in the development and progression of atherosclerosis, including endothelial dysfunction and oxidative modification of low-density lipoprotein (oxLDL) [6, 7]. ROS triggers LDL cholesterol oxidation to form oxLDL, resulting in the upregulated expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), an endothelial cell receptor for oxLDL [7]. Upregulated LOX-1 expression has been found in many pathological diseases, including hypercholesterolaemia [7]

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