Central Blockade of E-Prostanoid 3 Receptor Ameliorated Hypertension Partially by Attenuating Oxidative Stress and Inflammation in the Hypothalamic Paraventricular Nucleus of Spontaneously Hypertensive Rats

Wang, Fangfang; Ba, Juan; Yu, Xiao-Jing; Shi, Xiao-Lian; Liu, Jinjun; Liu, Kaili; Fu, Li-Yan; Su, Qing; Li, Hong-Bao; Kang, Kai; Yi, Qiu-Yue; Wang, Shuqiu; Gao, Hong-Li; Qi, Jie; Liu, Ying; Zhu, Guo‐Qing; Kang, Yu-Ming

doi:10.1007/s12012-020-09619-w

Cited by 14 publications

(15 citation statements)

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“…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.

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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.

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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.

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“…The PVN in the hypothalamus is a crucial BP regulation center [205], controlling other important nuclei and their circuits in the CNS, especially the rostroventrolateral medulla and nucleus tractus solitarius in the hindbrain, which is necessary for BP control [206][207][208]. Several studies have reported elevated proinflammatory cytokines expression in the PVN of animal hypertension models [209][210][211][212][213]. Further, the microinjection of inflammatory cytokines, such as TNF-α or IL-1β, into the PVN results in increased sympathetic outflow and increased afferent cardiac sympathetic reflex associated with an elevated BP [214].…”

Section: Hypertension and Hypothalamic Inflammationmentioning

confidence: 99%

Hypothalamic inflammation in metabolic disorders and aging

Bhusal

Rahman

Suk

2021

Cell. Mol. Life Sci.

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The hypothalamus is a critical brain region for the regulation of energy homeostasis. Over the years, studies on energy metabolism primarily focused on the neuronal component of the hypothalamus. Studies have recently uncovered the vital role of glial cells as an additional player in energy balance regulation. However, their inflammatory activation under metabolic stress condition contributes to various metabolic diseases. The recruitment of monocytes and macrophages in the hypothalamus helps sustain such inflammation and worsens the disease state. Neurons were found to actively participate in hypothalamic inflammatory response by transmitting signals to the surrounding non-neuronal cells. This activation of different cell types in the hypothalamus leads to chronic, low-grade inflammation, impairing energy balance and contributing to defective feeding habits, thermogenesis, and insulin and leptin signaling, eventually leading to metabolic disorders (i.e., diabetes, obesity, and hypertension). The hypothalamus is also responsible for the causation of systemic aging under metabolic stress. A better understanding of the multiple factors contributing to hypothalamic inflammation, the role of the different hypothalamic cells, and their crosstalks may help identify new therapeutic targets. In this review, we focus on the role of glial cells in establishing a cause-effect relationship between hypothalamic inflammation and the development of metabolic diseases. We also cover the role of other cell types and discuss the possibilities and challenges of targeting hypothalamic inflammation as a valid therapeutic approach.

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“…PGE2-EP3 signaling axis plays an important role in modulating brain injury, inflammation, and neurologic functional recovery after ICH or ischemia stroke [16,20,21,54,56]. EP3 inhibition improved oxidative stress injury and apoptosis [21,37,[58][59][60][61]. We consistently demonstrated that the endogenous expression of PGE2 and its receptors EP1-4 were increased in the ipsilateral brain hemisphere after SAH.…”

Section: Discussionmentioning

confidence: 52%

Inhibition of Prostaglandin E2 Receptor EP3 Attenuates Oxidative Stress and Neuronal Apoptosis Partially by Modulating p38MAPK/FOXO3/Mul1/Mfn2 Pathway after Subarachnoid Hemorrhage in Rats

Liu

Huang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Oxidative stress and neuronal apoptosis contribute to pathological processes of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies demonstrated that the inhibition of prostaglandin E2 receptor EP3 suppressed oxidative stress and apoptotic effects after Alzheimer’s disease and intracerebral hemorrhage. This study is aimed at investigating the antioxidative stress and antiapoptotic effect of EP3 inhibition and the underlying mechanisms in a rat mode of SAH. A total of 263 Sprague–Dawley male rats were used. SAH was induced by endovascular perforation. Selective EP3 antagonist L798106 was administered intranasally at 1 h, 25 h, and 49 h after SAH induction. EP3 knockout CRISPR and FOXO3 activation CRISPR were administered intracerebroventricularly at 48 h prior to SAH, while selective EP3 agonist sulprostone was administered at 1 h prior to SAH. SAH grade, neurological deficits, western blots, immunofluorescence staining, Fluoro-Jade C staining, TUNEL staining, 8-OHdG staining, and Nissl staining were conducted after SAH. The expression of endogenous PGES2 increased and peaked at 12 h while the expression of EP1, EP2, EP3, EP4, and Mul1 increased and peaked at 24 h in the ipsilateral brain after SAH. EP3 was expressed mainly in neurons. The inhibition of EP3 with L798106 or EP3 KO CRISPR ameliorated the neurological impairments, brain tissue oxidative stress, and neuronal apoptosis after SAH. To examine potential downstream mediators of EP3, we examined the effect of the increased expression of activated FOXO3 following the administration of FOXO3 activation CRISPR. Mechanism studies demonstrated that L798106 treatment significantly decreased the expression of EP3, p-p38, p-FOXO3, Mul1, 4-HNE, Bax, and cleaved caspase-3 but upregulated the expression of Mfn2 and Bcl-2 in SAH rats. EP3 agonist sulprostone or FOXO3 activation CRISPR abolished the neuroprotective effects of L798106 and its regulation on expression of p38MAPK/FOXO3/Mul1/Mfn2 in the ipsilateral brain after SAH. In conclusion, the inhibition of EP3 by L798106 attenuated oxidative stress and neuronal apoptosis partly through p38MAPK/FOXO3/Mul1/Mfn2 pathway post-SAH in rats. EP3 may serve as a potential therapeutic target for SAH patients.

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Central Blockade of E-Prostanoid 3 Receptor Ameliorated Hypertension Partially by Attenuating Oxidative Stress and Inflammation in the Hypothalamic Paraventricular Nucleus of Spontaneously Hypertensive Rats

Cited by 14 publications

References 50 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

Hypothalamic inflammation in metabolic disorders and aging

Inhibition of Prostaglandin E2 Receptor EP3 Attenuates Oxidative Stress and Neuronal Apoptosis Partially by Modulating p38MAPK/FOXO3/Mul1/Mfn2 Pathway after Subarachnoid Hemorrhage in Rats

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