Neuroinflammation contributes to autophagy flux blockage in the neurons of rostral ventrolateral medulla in stress-induced hypertension rats

Du, Dongshu; Hu, Li; Wu, Jing‐Yun; Wu, Qin; Cheng, Wenjing; Guo, Yuhong; Guan, Ruijuan; Wang, Yahui; Chen, Xingxin; Yan, Xanxia; Zhu, Dawei; Wang, Ji‐Jiang; Zhang, Shutian; Guo, Yan-Fang; Xia, Chunmei

doi:10.1186/s12974-017-0942-2

Cited by 52 publications

(73 citation statements)

References 48 publications

(73 reference statements)

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“…It is well known that the RVLM is a key region for central control of sympathetic outflow and plays a crucial role in maintaining resting BP and sympathetic tone [33,34]. The tonic activity of the RVLM is related to the interplay of a number of neurotransmitters and neuromodulators in these sympathetic neurons.…”

Section: Discussionmentioning

confidence: 99%

Exercise Training Attenuates Proinflammatory Cytokines, Oxidative Stress and Modulates Neurotransmitters in the Rostral Ventrolateral Medulla of Salt-Induced Hypertensive Rats

Huo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Exercise training (ExT) was associated with cardiovascular diseases including hypertension. The rostral ventrolateral medulla (RVLM) is a key region for central control of blood pressure and sympathetic nerve activity. Therefore, this study aimed to investigate the mechanisms within RVLM that can influence exercise training induced effects in salt-induced hypertension. Methods: Male Wistar rats were fed with a normal salt (0.3%) (NS) or a high salt (8%) (HS) diet for 12 weeks to induce hypertension. Then these rats were given moderate-intensity ExT for a period of 12 weeks. RVLM was used to determine glutamate and gamma-aminobutyric acid (HPLC), phosphorylated IKKβ, Fra-LI, 67-kDa isoform of glutamate decarboxylase (GAD67), proinflammatory cytokines (PIC) and NADPH-oxidase (NOX) subunits expression (Immunohistochemistry and Immunofluorescence, Western blotting). PIC and NF-κB p65 activity in the plasma were evaluated by ELISA studies. Renal sympathetic nerve activity (RSNA) was recorded and analyzed using the PowerLab system. Results: High salt diet resulted in increased mean arterial pressure and cardiac hypertrophy. These high salt diet rats had higher RVLM levels of glutamate, PIC, phosphorylated IKKβ, NF-κB p65 activity, Fra-LI, superoxide, NOX-2 (gp91^phox) and 4, and lower RVLM levels of gamma-aminobutyric acid and GAD67, and higher plasma levels of PIC, norepinephrine, and higher RSNA. ExT attenuated these changes in salt-induced hypertensive rats. Conclusions: These findings suggest that high salt diet increases the activity of NF-κB and the levels of PIC and oxidative stress, and induces an imbalance between excitatory and inhibitory neurotransmitters in the RVLM. ExT attenuates hypertension and cardiac hypertrophy partially mediated by attenuating oxidative stress and modulating neurotransmitters in the RVLM.

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Section: Discussionmentioning

confidence: 99%

Exercise Training Attenuates Proinflammatory Cytokines, Oxidative Stress and Modulates Neurotransmitters in the Rostral Ventrolateral Medulla of Salt-Induced Hypertensive Rats

Huo

et al. 2018

Cell Physiol Biochem

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“…Here, we reveal that rhythms in CLOCK gene observed in microglia isolated from the RVLM of are disrupted in SIH rats. Second, we demonstrate that the sustained high It was noted that activated microglia are the major trigger of neuroinflammation and oxidative stress, which are associated with sympathetic excitation and hypertension in rats [2].…”

Section: Discussionmentioning

confidence: 64%

“…There were randomly divided into the following groups: normotensive rats (control), stress-induced hypertension (SIH), SIH+EX 527 (the selective Sirt1 inhibitor) (5 mg/kg, injected intraperitoneally once daily following the same routine) [11], SIH+SRT1720 (the selective Sirt1 activator) (100 mg/kg, injected intraperitoneally once daily following the same routine) [12]. The SIH model of rat was established as previously described [2]. Sample size in this section of the study consisted of 6 rats per group.…”

Section: Animalsmentioning

confidence: 99%

“…Evidence shows that chronic psychosocial stresses activate various neurogenic pathways such as sympathetic nervous system (SNS), which is pivotal in triggering stress-induced cardiac and vascular events [1]. Our previous studies identified that interventions of electric foot-shock combined with noise stress induced a chronic increase in systolic blood pressure (SBP) in rats [2]. The sympathetic outflow is controlled by important nuclei and their circuits in the central nervous system (CNS), critically the hypothalamic paraventricular nucleus (PVN), the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitaries in hindbrain [3].…”

Section: Introductionmentioning

confidence: 99%

“…Increased microglia (MG) activation and neuroinflammation within autonomic brain regions have been implicated in stress-induced hypertension (SIH). Our previous study showed that central anti-inflammatory treatment by minocycline significantly alleviated SIH [2]. The alarmin high mobility group box-1 (HMGB1) has been implicated as a key factor mediating neuroinflammatory processes.…”

Section: Introductionmentioning

confidence: 99%

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CLOCK-induced upregulated HMGB1 resulting in circadian rhythms disruption of inflammatory microglia contributes to non-dipper hypertension in stressed rats

Zhang

Xia

2020

Preprint

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Increased microglia activation and neuroinflammation within autonomic brain regions have been implicated in stress-induced hypertension (SIH). The circadian clock affects physiological cellular and biological processes, including blood pressure (BP) control, but the mechanisms remain unclear. Microglia possess endogenous timekeeping mechanisms regulate immune responses. Here, we explore whether SIH is associated with disrupted diurnal rhythms in microglia proinflammatory factors (PICs) releasing. We found that SIH exhibit diminished BP circadian rhythms, which showed non-dipper hypertension. Microglia isolated from the rostral ventrolateral medulla (RVLM) of SIH rats had aberrant PICs releasing and CLOCK rhythms, while microglia from control rats exhibited robust rhythms of PICs expression both ex vivo and in vivo. In the RVLM, stress upregulated CLOCK expression which is independent of time of day in comparison with that of control. We further identified that upregulated CLOCK depressed sirt1 expression thereby increased oxidative stress-related HMGB1-PICs releasing in microglia in RVLM of SIH rats. In conclusion, the disrupts intrinsic circadian rhythms of microglia-derived PICs releasing involves in pathogeneses of non-dipper hypertension in stressed rats. Highlights• The aberrant rhythms CLOCK gene induced increased HMGB expression in microglia in the RVLM of stress-induced hypertension rats.• Aberrant CLOCK depressed sirt1 expression, which resulted in oxidative stress initiated inflammatory HMGB1 activation in microglia in RVLM of stress-induced hypertension rats.• The disrupts intrinsic circadian rhythms of microglia-derived inflammatory factor releasing in the RVLM involving in pathogeneses of non-dipper hypertension. Graphical abstractAbnormal CLOCK-sirt1-HMGB1 caused the aberrant circadian rhythms of microglial inflammatory factors releasing contributes to non-dipper hypertension. The disrupted circadian of CLOCK resulted in HMGB1 activation via sirt1-dependent oxidative stress in the RVLM.

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Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer’s disease patients

et al. 2020

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of misfolded proteins, amyloid-β (Aβ) aggregates, and neuroinflammation in the brain. Microglial cells are key players in the context of AD, being capable of releasing cytokines in response to Aβ and degrading aggregated proteins by mechanisms involving the ubiquitin-proteasome system and autophagy. Here, we present in vivo and in vitro evidence showing that microglial autophagy is affected during AD progression. PDAPPJ20 mice-murine model of AD-exhibited an accumulation of the autophagy receptor p62 and ubiq-uitin+ aggregates in Iba1+ microglial cells close to amyloid deposits in the hippocampus. Moreover, cultured microglial BV-2 cells showed an enhanced autophagic flux during a 2-h exposure to fibrillar Aβ, which was decreased if the exposure was prolonged to 24 h, a condition analogous to the chronic exposure to Aβ in the human pathology. The autophagic impairment was also associated with lysosomal damage, depicted by membrane permeabilization as shown by the presence of the acid hydrolase cathepsin-D in cytoplasm and altered LysoTracker staining. These results are compatible with microglial exhaustion caused by proinflammatory conditions and persistent exposure to aggregated Aβ peptides. In addition, we found LC3positive autophagic vesicles accumulated in phagocytic CD68+ microglia in human AD brain samples, suggesting defective autophagy in microglia of AD brain. Our results indicate that the capacity of microglia to degrade Aβ and potentially other proteins through autophagy may be negatively affected as the disease progresses. Preserving autophagy in microglia thus emerges as a promising approach for treating AD.

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Neuroinflammation contributes to autophagy flux blockage in the neurons of rostral ventrolateral medulla in stress-induced hypertension rats

Cited by 52 publications

References 48 publications

Exercise Training Attenuates Proinflammatory Cytokines, Oxidative Stress and Modulates Neurotransmitters in the Rostral Ventrolateral Medulla of Salt-Induced Hypertensive Rats

Exercise Training Attenuates Proinflammatory Cytokines, Oxidative Stress and Modulates Neurotransmitters in the Rostral Ventrolateral Medulla of Salt-Induced Hypertensive Rats

CLOCK-induced upregulated HMGB1 resulting in circadian rhythms disruption of inflammatory microglia contributes to non-dipper hypertension in stressed rats

Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer’s disease patients

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