Blockade of TLR4 Within the Paraventricular Nucleus Attenuates Blood Pressure by Regulating ROS and Inflammatory Cytokines in Prehypertensive Rats

Wang, Molin; Yu, Xiao-Jing; Li, Xiaoguang; Pang, Dezhi; Su, Qing; Saahene, Roland Osei; Li, Hong-Bao; Mao, Xu-Ying; Liu, Kaili; Fu, Li-Yan; Li, Ying; Zhu, Guo‐Qing; Kang, Yu-Ming

doi:10.1093/ajh/hpy074

Cited by 31 publications

(17 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased ROS production can be found in the PVN of hypertensive animals (Wang et al, 2018(Wang et al, , 2021Yang et al, 2020). The oxidative stress caused by the imbalance of ROS production and removal contributes to the advancement of inflammatory responses and hyperactivity of sympathetic nerves, and promotes the progression of hypertension.…”

Section: Discussionmentioning

confidence: 99%

Effects of Nrf1 in Hypothalamic Paraventricular Nucleus on Regulating the Blood Pressure During Hypertension

Xiao

Liu

et al. 2021

Front. Neurosci.

Self Cite

View full text Add to dashboard Cite

The incidence rate and mortality of hypertension increase every year. Hypothalamic paraventricular nucleus (PVN) plays a critical role on the pathophysiology of hypertension. It has been demonstrated that the imbalance of neurotransmitters including norepinephrine (NE), glutamate (Glu) and γ-aminobutyric acid (GABA) are closely related to sympathetic overactivity and pathogenesis of hypertension. N-methyl-D-aspartate receptor (NMDAR), consisting of GluN1 and GluN2 subunits, is considered to be a glutamate-gated ion channel, which binds to Glu, and activates neuronal activity. Studies have found that the synthesis of respiratory chain enzyme complex was affected and mitochondrial function was impaired in spontaneously hypertensive rats (SHR), further indicating that mitochondria is associated with hypertension. Nuclear respiratory factor 1 (Nrf1) is a transcription factor that modulates mitochondrial respiratory chain and is related to GluN1, GluN2A, and GluN2B promoters. However, the brain mechanisms underlying PVN Nrf1 modulating sympathoexcitation and blood pressure during the development of hypertension remains unclear. In this study, an adeno-associated virus (AAV) vector carrying the shRNA targeting rat Nrf1 gene (shNrf1) was injected into bilateral PVN of male rats underwent two kidneys and one clip to explore the role of Nrf1 in mediating the development of hypertension and sympathoexcitation. Administration of shNrf1 knocked down the expression of Nrf1 and reduced the expression of excitatory neurotransmitters, increased the expression of inhibitory neurotransmitters, and reduced the production of reactive oxygen species (ROS), and attenuated sympathoexcitation and hypertension. The results indicate that knocking down Nrf1 suppresses sympathoexcitation in hypertension by reducing PVN transcription of NMDAR subunits (GluN1, GluN2A, and GluN2B), rebalancing PVN excitatory and inhibitory neurotransmitters, inhibiting PVN neuronal activity and oxidative stress, and attenuating sympathetic activity.

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of Nrf1 in Hypothalamic Paraventricular Nucleus on Regulating the Blood Pressure During Hypertension

Xiao

Liu

et al. 2021

Front. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…TLR4 has been recognized as an important regulator for NF-κB (Li et al, 2016). Growing pieces of evidence have shown that activated TLR4 within the PVN contributes to RSNA in salt-sensitive hypertension, by which the MyD88 is activated and subsequentially lead to the activation of NF-κB (Li et al, 2016; Wang M.L. et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Exercise Training Attenuates Hypertension Through TLR4/MyD88/NF-κB Signaling in the Hypothalamic Paraventricular Nucleus

et al. 2019

Front. Neurosci.

Self Cite

View full text Add to dashboard Cite

Exercise training (ExT) is beneficial for cardiovascular health, yet the central mechanism by which aerobic ExT attenuates the hypertensive responses remains unclear. Activation of pro-inflammatory cytokines (PICs) in the hypothalamic paraventricular nucleus (PVN) is important for the sympathoexcitation and hypertensive response. We thus hypothesized that aerobic ExT can decrease the blood pressure of hypertensive rats by reducing the levels of PICs through TLR4/MyD88/NF-κB signaling within the PVN. To examine this hypothesis, two-kidney-one-clip (2K1C) renovascular hypertensive rats were assigned to two groups: sedentary or exercise training and examined for 8 weeks. At the same time, bilateral PVN infusion of vehicle or TAK242, a TLR4 inhibitor, was performed on both groups. As a result, the systolic blood pressure (SBP), renal sympathetic nerve activity (RSNA) and plasma levels of norepinephrine (NE), epinephrine (EPI) were found significantly increased in 2K1C hypertensive rats. These rats also had higher levels of Fra-like activity, NF-κB p65 activity, TLR4, MyD88, IL-1β and TNF-α in the PVN than SHAM rats. Eight weeks of ExT attenuated the RSNA and SBP, repressed the NF-κB p65 activity, and reduced the increase of plasma levels of NE, EPI, and the expression of Fra-like, TLR4, MyD88, IL-1β and TNF-α in the PVN of 2K1C rats. These findings are highly similar to the results in 2K1C rats with bilateral PVN infusions of TLR4 inhibitor (TAK242). This suggests that 8 weeks of aerobic ExT may decrease blood pressure in hypertensive rats by reducing the PICs activation through TLR4/MyD88/NF-κB signaling within the PVN, and thus delays the progression of 2K1C renovascular hypertension.

show abstract

“…ROS can act as key modulators of increased neuronal activity in the PVN of rats with hypertension, heart failure or metabolic syndrome [29–32]. More importantly, ROS in the PVN can modulate AAR [25].…”

Section: Discussionmentioning

confidence: 99%

Adipose afferent reflex is enhanced by TNFα in paraventricular nucleus through NADPH oxidase-dependent ROS generation in obesity-related hypertensive rats

et al. 2019

Self Cite

View full text Add to dashboard Cite

Background The adipose afferent reflex (AAR), a sympatho-excitatory reflex, can promote the elevation of sympathetic nerve activity (SNA) and blood pressure (BP). Inflammation in the paraventricular nucleus (PVN) involves sympathetic abnormality in some cardiovascular diseases such as hypertension. This study was designed to explore the effects of tumor necrosis factor alpha (TNFα) in the PVN on the AAR and SNA in rats with obesity-related hypertension (OH) induced by a high-fat diet for 12 weeks. Methods Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were continuously recorded in anesthetized rats, and their responses to capsaicin (CAP) stimulation of the right inguinal white adipose tissue were used to evaluate the AAR. Results Compared to the control rats, the systolic blood pressure (SBP), plasma norepinephrine (NE, indicating SNA) and TNFα levels, TNFα mRNA and protein levels, reactive oxygen species (ROS) content and NADPH oxidase activity in the PVN were significantly elevated in rats with OH. TNFα in the PVN markedly enhanced sympathoexcitation and AAR. Moreover, the enhancement of AAR caused by TNFα can be significantly strengthened by the pretreatment of diethyldithiocarbamate (DETC), a superoxide dismutase inhibitor, but attenuated by TNF-α receptor antagonist R-7050, superoxide scavenger PEG-SOD and NADPH oxidase inhibitor apocynin (Apo) in rats with OH. Acute microinjection of TNF-α into the PVN significantly increased the activity of NADPH oxidase and ROS levels in rats with OH, which were effectively blocked by R-7050. Furthermore, our results also showed that the increased levels of ROS, TNFα and NADPH oxidase subunits mRNA and protein in the PVN of rats with OH were significantly reversed by pentoxifylline (PTX, 30 mg/kg daily ip; in 10% ethanol) application, a cytokine blocker, for a period of 5 weeks. PTX administration also significantly decreased SBP, AAR and plasma NE levels in rats with OH. Conclusions TNFα in the PVN modulates AAR and contributes to sympathoexcitation in OH possibly through NADPH oxidase-dependent ROS generation. TNFα blockade attenuates AAR and sympathoexcitation that unveils TNFα in the PVN may be a possible therapeutic target for the intervention of OH.

show abstract

Blockade of TLR4 Within the Paraventricular Nucleus Attenuates Blood Pressure by Regulating ROS and Inflammatory Cytokines in Prehypertensive Rats

Abstract: Salt-induced prehypertension is partly due to the upregulation of TLR4 in PVN. Blockade of TLR4 in the brain reduced salt-induced prehypertension response, possibly through downregulation of ROS and PICs expression, and the restorage of neurotransmitter balance in the PVN.

Cited by 31 publications

References 45 publications

Effects of Nrf1 in Hypothalamic Paraventricular Nucleus on Regulating the Blood Pressure During Hypertension

Effects of Nrf1 in Hypothalamic Paraventricular Nucleus on Regulating the Blood Pressure During Hypertension

Exercise Training Attenuates Hypertension Through TLR4/MyD88/NF-κB Signaling in the Hypothalamic Paraventricular Nucleus

Adipose afferent reflex is enhanced by TNFα in paraventricular nucleus through NADPH oxidase-dependent ROS generation in obesity-related hypertensive rats

Contact Info

Product

Resources

About