Hypertensive Rats Treated Chronically With Nω-Nitro-L-Arginine Methyl Ester (L-NAME) Induced Disorder of Hepatic Fatty Acid Metabolism and Intestinal Pathophysiology.

Bo Li,Jie Su,Shan Xiong,Rong Luo,Fu-Chen Zhou,Ye-Hui Chen,Shan-Shan Lei,Gui-Yuan Lv,Su-Hong Chen,Xiang Zheng,Jing-Jing Yu,Dorota Kołodyńska,Yu-Zhi Wang,Xinglishang He,Lin-Zi Li,Ning-Yu Zhang

doi:10.3389/fphar.2019.01677

Abstract

Nω-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension and liver injury. This study aimed at investigating the changes of liver lipometabonomics and exploring the underlying mechanisms of liver injury in the L-NAME-treated rats. The male Sprague-Dawley (SD) rats were treated with L-NAME (40 mg/kg, p.o.) for 8 weeks. After that, the liver, aorta, fecal, and serum were collected for analysis. The results showed that L-NAME induced hypertension and disordered the endothelial nitric oxide synthase (eNOS)-NO pathway in the treated rats. L-NAME could also increase the levels of serum total cholesterol (TC), triglyceride (TG), alanine transaminase (ALT), and aspartate transaminase (AST). The multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) analysis showed that L-NAME could induce significant changes of the total hepatic lipids and most hepatic triglycerides, as well as fatty acid (FA). A positive correlation was found between the blood pressure and TAG. Immunofluorescence and Western-Blot experiments indicated that the L-NAME treatment significantly influenced some FA β-oxidation, desaturation, and synthesis-related proteins. The increase of intestinal inflammation, decrease of microcirculation and tight junction proteins, as well as alterations of microbial communities were observed in the L-NAME induced hypertensive rats, as well as alterations of microbial communities were notable correlation to TAG and FA species. This study demonstrated that the L-NAME-induced hypertensive rats exhibiting liver injury were the joint action of hepatic abnormal fatty acid metabolism and microcirculation disorder. Furthermore, the gut microflora, as well as the changes of FA β-oxidation (ACOX, CPT1α), desaturation (SCD-1), and synthesis (FAS) may be the potential mechanisms for abnormal fatty acid metabolism.

Highlights

Hypertension is one of the most common risk factors affecting cardiovascular disease
This study demonstrated that the L-NAME-treated group (L-NAME)-induced hypertensive rats exhibiting liver injury were the joint action of hepatic abnormal fatty acid metabolism and microcirculation disorder
We found that the expression of endothelial nitric oxide synthase (eNOS) in aorta endothelium was significantly reduced with thickening of vascular wall (Figure 1D), and L-NAME caused a significant decrease of serum nitric oxide (NO) level in rats (Figure 1E) (P < 0.05)

Summary

Introduction

Hypertension is one of the most common risk factors affecting cardiovascular disease. Hypertension, or high blood pressure (BP), is defined as a sustained systolic pressure ≥ 130 mmHg or diastolic pressure ≥ 80 mmHg according to the 2017 American College of Cardiology/American Heart Association (ACC/AHA) High Blood Pressure Guideline (Wang et al, 2018). The epidemiologic research shows that the occurrence of hypertension displays a consistent increasing trend. In China, the prevalence of hypertension, based on the 2017 ACC/AHA guidelines, may be twice incidence at 46.4% (Wang et al, 2018). At least 760 million people worldwide die per year from cardiovascular diseases associated with hypertension, representing 13.5% of the total causes of death (Lawes et al, 2008; Li et al, 2018a)

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