Bilateral Paraventricular Nucleus Upregulation of Extracellular Superoxide Dismutase Decreases Blood Pressure by Regulation of the NLRP3 and Neurotransmitters in Salt-Induced Hypertensive Rats.

Qing Su,Xiao-Min Wang,Guo-Qing Zhu,Hong-Bao Li,Yu-Ming Kang,Yan Zhang,Ying Li,Kai-Li Liu,Jie Qi,Juan Bai,Xiao-Jing Yu,Nianping Zhang

doi:10.3389/fphar.2021.756671

Abstract

Aims: Long-term salt diet induces the oxidative stress in the paraventricular nucleus (PVN) and increases the blood pressure. Extracellular superoxide dismutase (Ec-SOD) is a unique antioxidant enzyme that exists in extracellular space and plays an essential role in scavenging excessive reactive oxygen species (ROS). However, the underlying mechanism of Ec-SOD in the PVN remains unclear. Methods: Sprague–Dawley rats (150–200 g) were fed either a high salt diet (8% NaCl, HS) or normal salt diet (0.9% NaCl, NS) for 6 weeks. Each group of rats was administered with bilateral PVN microinjection of AAV-Ec-SOD (Ec-SOD overexpression) or AAV-Ctrl for the next 6 weeks. Results: High salt intake not only increased mean arterial blood pressure (MAP) and the plasma noradrenaline (NE) but also elevated the NAD(P)H oxidase activity, the NAD(P)H oxidase components (NOX2 and NOX4) expression, and ROS production in the PVN. Meanwhile, the NOD-like receptor protein 3 (NLRP3)–dependent inflammatory proteins (ASC, pro-cas-1, IL-β, CXCR, CCL2) expression and the tyrosine hydroxylase (TH) expression in the PVN with high salt diet were higher, but the GSH level, Ec-SOD activity, GAD67 expression, and GABA level were lower than the NS group. Bilateral PVN microinjection of AAV-Ec-SOD decreased MAP and the plasma NE, reduced NAD(P)H oxidase activity, the NOX2 and NOX4 expression, and ROS production, attenuated NLRP3-dependent inflammatory expression and TH, but increased GSH level, Ec-SOD activity, GAD67 expression, and GABA level in the PVN compared with the high salt group. Conclusion: Excessive salt intake not only activates oxidative stress but also induces the NLRP3-depensent inflammation and breaks the balance between inhibitory and excitability neurotransmitters in the PVN. Ec-SOD, as an essential anti-oxidative enzyme, eliminates the ROS in the PVN and decreases the blood pressure, probably through inhibiting the NLRP3-dependent inflammation and improving the excitatory neurotransmitter release in the PVN in the salt-induced hypertension.

Highlights

Long-term excessive salt intake is one of the high-risk environmental factors responsible for the blood pressure regulation and the major dietary determinant for cardiovascular diseases especially the salt-induced hypertension
The results showed that excessive salt intake increased mean arterial blood pressure (MAP) from the second week
The MAP was higher in salt-induced group than in normal salt group (99.83 ± 6.42 mmHg vs. 136.51 ± 5.67 mmHg, p < 0.05)

Summary

Introduction

Long-term excessive salt intake is one of the high-risk environmental factors responsible for the blood pressure regulation and the major dietary determinant for cardiovascular diseases especially the salt-induced hypertension. Excessive sodium intake raises the endothelial NAD(P)H oxidase-dependent oxidative stress, resulting in the excessive amount of superoxide anion production that is mainly injurious to the vasculature (Matsui et al, 2006; Fujita et al, 2007; Kido et al, 2008). All of those disturb the signaling pathways for endothelial nitric oxide synthase (NOS) activity so far as to make a reduction of the vascular NO bioavailability and protective function for the cardiovascular system (Channon, 2004; Boegehold, 2013). High salt intake is closely associated with hypertension and cardiovascular diseases

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Discussion

Conclusion