Folate Reverses NF-κB p65/Rela/IL-6 Level Induced by Hyperhomocysteinemia in Spontaneously Hypertensive Rats.

Lihua Zhang,Rui Xu,Zhongliang Li,Changcheng Xing,Ning Gao

doi:10.3389/fphar.2021.651582

Abstract

Hyperhomocysteinemia (HHcy) is derived from the abnormal metabolism of homocysteine (Hcy) and is related to metabolic-related diseases. In addition, HHcy combined with hypertension increases the risk of cardiovascular diseases (CVD). However, the mechanism of HHcy aggravating hypertensive arterial damage and the efficacy of folate (FA) as a beneficial supplement have not been fully elucidated. In this study, we established a rat HHcy model and a hypertension combined with HHcy model. Rat tail artery blood pressure (BP), plasma Hcy, serum superoxide dismutase (SOD), and malondialdehyde (MDA) were measured. Rat thoracic aorta was for pathological analysis after 12 weeks of the experiment. The relative expression levels of oxidative stress and immune/inflammation in rat arterial tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The results demonstrated that the relative expression levels of oxidative stress and immune/inflammation were the highest in the hypertension combined with HHcy group, followed by the hypertension group. Compared with the hypertension group, the hypertension combined with HHcy group up-regulated the expression levels of interleukin-6 (IL-6) and nuclear factor-κ-gene binding (NF-κB) p65/Rela, but not NADPH oxidase (Nox). Furthermore, folate inhibited the expression of IL-6 and NF-κB p65/Rela, reduced the levels of MDA and HHcy, but significantly increased the SOD level. In conclusion, HHcy synergistically aggravated the arterial damage factor of hypertension through immune/inflammatory response. However, folate demonstrated anti-inflammatory properties and reversed the NF-κB p65/Rela/IL-6 level induced by HHcy in hypertensive rats.

Highlights

Epidemiological studies have found that the incidence of hypertension combined with hyperhomocysteinemia (HHcy) is relatively high in China (Li et al, 2007)
Hypertension is the main contributor for the pathological changes of the arteries in the hypertension combined with HHcy rats, and hypertension itself is more important than HHcy in inducing oxidative stress and immune/inflammation to cause arterial damage
HHcy increased the levels of oxidative stress in the circulation, it did not induce the high expression of NOX2 and NOX4 in rat arterial tissue

Summary

Introduction

Epidemiological studies have found that the incidence of hypertension combined with hyperhomocysteinemia (HHcy) is relatively high in China (Li et al, 2007). HHcy significantly increases the incidence of cardiovascular disease (CVD) (Chen et al, 1963). Some scholars propose that HHcy is a marker (Fu et al, 2017) of abnormal methyl metabolism (including methionine metabolism and folate metabolism) and/or abnormal transsulfur metabolism in the body. Another statement indicates that the unique thiol structure of HHcy/Hcy has molecular toxicity and is the cause of CVD (Gurda et al, 2015)

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Results

Conclusion