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Liu T, Wang L, Tong L, Ren Z, Zhao B, Liu H, Lu W, Zhang H, Zhang S, Du D. PDZD8 Dysregulation Mediates RVLM Neuronal Hyperexcitation Via Activation of Ca 2+-Calpain-2 Signaling in Stress-Induced Hypertension. Mol Neurobiol 2025:10.1007/s12035-025-05081-3. [PMID: 40418411 DOI: 10.1007/s12035-025-05081-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 05/16/2025] [Indexed: 05/27/2025]
Abstract
Neuronal hyperexcitation in the rostral ventrolateral medulla (RVLM) is crucial in the pathogenesis of stress-induced hypertension (SIH). PDZD8 connects endoplasmic reticulum (ER) to mitochondria, and is involved in SIH through regulating RVLM neuronal mitochondrial physiological function. However, the underlying mechanisms of the PDZD8 dysregulation-mediated mitochondrial dysfunction of RVLM neurons, affecting neuronal excitability during SIH, are not fully clarified. An SIH rat model was established by administering intermittent electric foot shocks combined with noise exposure for 2 h twice daily over a period of 15 days. The impacts of PDZD8 on regulating RVLM neuronal ER stress, mitochondrial function, apoptosis, and blood pressure (BP) of SIH rats, along with the related signaling pathway, were explored through using in-vivo and in-vitro techniques like RVLM microinjection, Western blot, flow cytometry, and immunofluorescence. We demonstrated that the ratio of c-Fos-positive tyrosine hydroxylase (TH) neurons, renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE) levels, BP, and heart rate (HR) increased in SIH rats. The activated neuronal ER stress, impaired mitochondrial function, and apoptosis were observed in the RVLM of SIH rats and PDZD8-deficient N2a cells. ER stress inhibitor (4-phenylbutyric acid, 4-PBA) administration effectively alleviated PDZD8 dysregulation-induced mitochondrial dysfunction and apoptosis. Mechanistically, PDZD8 negatively regulated Calpain-2 (CAPN2) expression through modulating cytoplasmic Ca2+ levels. In vitro, CAPN2 inhibition rescued PDZD8 deficiency-induced ER stress, mitochondrial dysfunction, and apoptosis. In vivo, PDZD8 upregulation in the RVLM of SIH rats attenuated neuronal ER stress, mitochondrial dysfunction, and apoptosis, thus reducing RVLM neuronal excitability, RSNA, plasma NE, BP, and HR. These effects were blocked by CAPN2 overexpression. Overall, this study revealed that PDZD8 dysregulation induced RVLM neuronal ER stress, mitochondrial damage, and apoptosis by activating the Ca2+-CAPN2 axis, playing a crucial pathological role in SIH progression.
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Affiliation(s)
- Tianfeng Liu
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai, 200444, China
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Linping Wang
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai, 200444, China
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Lei Tong
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Zhangyan Ren
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Bingjie Zhao
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Haisheng Liu
- Department of Preventive Medicine, Heze Medical College, Heze, 274000, Shandong, China
| | - Wen Lu
- Department of Preventive Medicine, Heze Medical College, Heze, 274000, Shandong, China
| | - Haili Zhang
- Department of Preventive Medicine, Heze Medical College, Heze, 274000, Shandong, China
| | - Shuai Zhang
- International Cooperation Laboratory of Molecular Medicine, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
- College of Agriculture and Bioengineering, Heze University, Heze, 274000, Shandong, China.
| | - Dongshu Du
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai, 200444, China.
- School of Life Sciences, Shanghai University, Shanghai, 200444, China.
- College of Life Sciences, Dezhou University, Dezhou, 253000, Shandong, China.
- Department of Preventive Medicine, Heze Medical College, Heze, 274000, Shandong, China.
- College of Agriculture and Bioengineering, Heze University, Heze, 274000, Shandong, China.
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Al-Shami AS, Abd Elkader HTAE, Moussa N, Essawy AE, Haroun M. Early-life bisphenol A exposure causes neuronal pyroptosis in juvenile and adult male rats through the NF-κB/IL-1β/NLRP3/caspase-1 signaling pathway: exploration of age and dose as effective covariates using an in vivo and in silico modeling approach. Mol Cell Biochem 2025; 480:2301-2330. [PMID: 38941031 PMCID: PMC11961519 DOI: 10.1007/s11010-024-05039-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 05/14/2024] [Indexed: 06/29/2024]
Abstract
Bisphenol A (BPA), a common endocrine-disrupting chemical, is found in a wide range of home plastics. Early-life BPA exposure has been linked to neurodevelopmental disorders; however, the link between neuroinflammation, pyroptosis, and the development of psychiatric disorders is rarely studied. The current study attempted to investigate the toxic effect of BPA on inflammatory and microglial activation markers, as well as behavioral responses, in the brains of male rats in a dose- and age-dependent manner. Early BPA exposure began on postnatal day (PND) 18 at dosages of 50 and 125 mg/kg/day. We started with a battery of behavioral activities, including open field, elevated plus- and Y-maze tests, performed on young PND 60 rats and adult PND 95 rats. BPA causes anxiogenic-related behaviors, as well as cognitive and memory deficits. The in vivo and in silico analyses revealed for the first time that BPA is a substantial activator of nuclear factor kappa B (NF-κB), interleukin (IL)-1β, -2, -12, cyclooxygenase-2, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, with higher beclin-1 and LC3B levels in BPA rats' PFC and hippocampus. Furthermore, BPA increased the co-localization of caspase-1 immunoreactive neurons, as well as unique neurodegenerative histopathological hallmarks. In conclusion, our results support the hypothesis that neuroinflammation and microglial activation are involved with changes in the brain after postnatal BPA exposure and that these alterations may be linked to the development of psychiatric conditions later in life. Collectively, our findings indicate that BPA triggers anxiety-like behaviors and pyroptotic death of nerve cells via the NF-κB/IL-1β/NLRP3/Caspase-1 pathway.
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Affiliation(s)
- Ahmed S Al-Shami
- Biotechnology Department, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt
| | | | - Nermine Moussa
- Biotechnology Department, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt
| | - Amina E Essawy
- Zoology Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Medhat Haroun
- Biotechnology Department, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt
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Zhang S, Huang Y, Han C, Chen M, Yang Z, Wang C. Circulating mitochondria carrying cGAS promote endothelial Secreted group IIA phospholipase A2-mediated neuroinflammation through activating astroglial/microglial Integrin-alphavbeta3 in subfornical organ to augment central sympathetic overdrive in heart failure rats. Int Immunopharmacol 2025; 144:113649. [PMID: 39586230 DOI: 10.1016/j.intimp.2024.113649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 11/27/2024]
Abstract
BACKGROUND Sympathoexcitation, a manifestation of heart-brain axis dysregulation, contributes to the progression of heart failure (HF). Our recent study revealed that circulating mitochondria (C-Mito), a newly identified mediator of multi-organ communication, promote sympathoexcitation in HF by aggravating endothelial cell (EC)-derived neuroinflammation in the subfornical organ (SFO), the cardiovascular autonomic neural center. The precise molecular mechanism by which C-Mito promotes SFO-induced endothelial neuroinflammation has not been fully elucidated. OBJECTIVE C-Mito carrying cGAS promote sympathoexcitation by targeting PLA2G2A in ECs of the SFO in HF rats. METHODS Male Sprague-Dawley (SD) rats received a subcutaneous injection of isoprenaline (ISO) at a dosage of 5 mg/kg/day for seven consecutive days to establish a HF model. C-Mito were isolated from HF rats and evaluated. The level of cGAS, a dsDNA sensor recently discovered to be directly localized on the outer membrane of mitochondria, was detected in C-Mito. C-Mito from HF rats (C-MitoHF) or control rats (C-MitoCtrl) were intravenously infused into HF rats. The accumulation of C-Mito in the ECs in the SFO was detected via double immunofluorescence staining. The SFO was processed for RNA sequencing (RNA-Seq) analysis. Secreted group IIA phospholipase A2 (PLA2G2A), the key gene involved in C-MitoHF-associated SFO dysfunction, was identified via bioinformatics analysis. Upregulation of PLA2G2A in the SFO ECs was assessed via immunofluorescence staining and immunoblotting, and PLA2G2A activity was evaluated. The interaction between cGAS and PLA2G2A was detected via co-immunoprecipitation. The dowstream molecular mechanisms of which PLA2G2A induced astroglial/microglial activation were also investigated. AAV9-TIE-shRNA (PLA2G2A) was introduced into the SFO to specifically knockdown endothelial PLA2G2A. Neuronal activation and glial proinflammatory polarization in the SFO were also evaluated. Renal sympathetic nerve activity (RSNA) was measured to evaluate central sympathetic output. Cardiac sympathetic hyperinnervation, myocardial remodeling, and left ventricular systolic function were assessed in C-Mito-treated HF rats. RESULTS Respiratory functional incompetence and oxidative damage were observed in C-MitoHF compared with C-MitoCtrl. Surprisingly, cGAS protein levels in C-MitoHF were significantly higher than those in C-MitoCtrl, while blocking cGAS with its specific inhibitor, RU.521, mitigated respiratory dysfunction and oxidative injury in C-MitoHF. C-Mito entered the ECs of the SFO in HF rats. RNA sequencing revealed that PLA2G2A is a key molecule for the induction of SFO dysfunction by C-MitoHF. The immunoblotting and immunofluorescence results confirmed that, compared with C-MitoCtrl, C-MitoHF increased endothelial PLA2G2A expression in the SFO of HF rats, which could be alleviated by attenuating C-MitoHF-localized cGAS. Furthermore, we found that cGAS directly interacts with PLA2G2A, increased the activity of PLA2AG2, which produced arachidonic acid, and also promoted PLA2G2A secretion in brain ECs. In addition, the inhibition of PLA2G2A in brain ECs significantly mitigated the proinflammatory effect of conditioned cell culture medium from C-MitoHF-treated ECs on astroglia and microglia. Also, we found that PLA2G2A secreted from ECs insulted by C-Mito induced neuroinflammation through activating astriglial/microglial Integrin-alphavbeta3 in the SFO, which further promote central sympathetic overdrive in HF rats. Specific knockdown of endothelial PLA2G2A in the SFO mitigated C-MitoHF-induced presympathetic neuronal sensitization, cardiac sympathetic hyperinnervation, RSNA activation, myocardial remodeling, and systolic dysfunction in HF rats. CONCLUSION C-Mito carrying cGAS promoted cardiac sympathoexcitation by directly targeting PLA2G2A in the ECs of the SFO in HF rats. Secreted PLA2G2A derived from ECs insulted by C-Mito induced neuroinflammation through activating astriglial/microglial Integrin-alphavbeta3 in the SFO, which further promote central sympathetic overdrive in HF rats. Our study indicated that inhibiting cGAS in C-Mito might be a potential treatment for central sympathetic overdrive in HF.
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Affiliation(s)
- Shutian Zhang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
| | - Yijun Huang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Chengzhi Han
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Maoxiang Chen
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Zhaohua Yang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
| | - Chunsheng Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
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Zhang S, Huang Y, Han C, Wang F, Chen M, Yang Z, Yang S, Wang C. Central SGLT2 mediate sympathoexcitation in hypertensive heart failure via attenuating subfornical organ endothelial cGAS ubiquitination to amplify neuroinflammation: Molecular mechanism behind sympatholytic effect of Empagliflozin. Int Immunopharmacol 2025; 145:113711. [PMID: 39647283 DOI: 10.1016/j.intimp.2024.113711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/22/2024] [Accepted: 11/22/2024] [Indexed: 12/10/2024]
Abstract
BACKGROUND Sodium/glucose co-transporter 2 (SGLT2) inhibitors have transformed heart failure (HF) treatment, offering sympatholytic effects whose mechanisms are not fully understood. Our previous studies identified Cyclic GMP-AMP synthase (cGAS)-derived neuroinflammation in the Subfornical organ (SFO) as a promoter of sympathoexcitation, worsening myocardial remodeling in HF. This research explored the role of central SGLT2 in inducing endothelial cGAS-driven neuroinflammation in the SFO during HF and assessed the impact of SGLT2 inhibitors on this process. METHODS Hypertensive HF was induced in mice via Angiotensin II infusion for four weeks. SGLT2 expression and localization in the SFO were determined through immunoblotting and double-immunofluorescence staining. AAV9-TIE-shRNA (SGLT2) facilitated targeted SGLT2 knockdown in SFO endothelial cells (ECs), with subsequent analyses via immunoblotting, staining, and co-immunoprecipitation to investigate interactions with cGAS, mitochondrial alterations, and pro-inflammatory pathway activation. Renal sympathetic nerve activity and heart rate variability were measured to assess sympathetic output, alongside evaluations of cardiac function in HF mice. RESULTS In HF model mice, SGLT2 levels are markedly raised in SFO ECs, disrupting mitochondrial function and elevating oxidative stress. SGLT2 knockdown preserved mitochondrial integrity and function, reduced inflammation, and highlighted the influence of SGLT2 on mitochondrial health. SGLT2's interaction with cGAS prevented its ubiquitination and degradation, amplifying neuroinflammation and HF progression. Conversely, Empagliflozin counteracted these effects, suggesting that targeting the SGLT2-cGAS interaction as a novel HF treatment avenue. CONCLUSION This study revealed that SGLT2 directly reduced cGAS degradation in brain ECs, enhancing neuroinflammation in the SFO, and promoting sympathoexcitation and myocardial remodeling. The significance of the central SGLT2-cGAS interaction in cardiovascular disease mechanisms is emphasized.
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Affiliation(s)
- Shutian Zhang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
| | - Yijun Huang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Chengzhi Han
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Fanshun Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Maoxiang Chen
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Zhaohua Yang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
| | - Shouguo Yang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
| | - Chunsheng Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
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Sun J, Chen Y, Zhao X, Niu Z, Gu Z, Yan Z, Wang W. Effect and interaction of PINK1 genetic polymorphisms and environmental factors on blood pressure in COEs-exposed workers. INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2024:1-12. [PMID: 39295235 DOI: 10.1080/09603123.2024.2403685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 09/09/2024] [Indexed: 09/21/2024]
Abstract
Coke oven emissions (COEs) contain a variety of polycyclic aromatic hydrocarbons (PAHs), which can cause damage to the human cardiovascular system. In addition, myocardial mitochondria are susceptible to damage in hypertensive patients. However, it is not clear whether genetic variation, in single nucleotide polymorphisms (SNPs) in PINK1 affects COEs exposure-induced abnormal blood pressure. We surveyed and tested 518 workers exposed to COEs and statistically analyzed them with SPSS 21.0 software. SBP was greater in the high-exposure group than in the low-exposure group. Generalized linear model analysis showed that the interaction of PINK1 rs3738136 (GA+AA) and COEs had an effect on SBP [β(95%CI) = -6.537(-12.072, -1.002), p = 0.021] and DBP [β(95%CI) = -4.811(-8.567, -1.056), p = 0.012]. This study is the first to identify the role of PINK1 rs3738136 in COE- induced abnormal blood pressure, and to prove that the abnormal blood pressure of workers is the result of environmental and genetic factors.
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Affiliation(s)
- Jing Sun
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou, Henan, China
| | - Yang Chen
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou, Henan, China
| | - Xiangkai Zhao
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou, Henan, China
| | - Zeming Niu
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou, Henan, China
| | - Zhiguang Gu
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou, Henan, China
| | - Zhaofan Yan
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou, Henan, China
| | - Wei Wang
- Department of Occupational Health and Occupational Diseases, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China
- The Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou, Henan, China
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Xia M, Wang T, Wang Y, Hu T, Chen D, Wang B. A neural perspective on the treatment of hypertension: the neurological network excitation and inhibition (E/I) imbalance in hypertension. Front Cardiovasc Med 2024; 11:1436059. [PMID: 39323755 PMCID: PMC11422145 DOI: 10.3389/fcvm.2024.1436059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 08/29/2024] [Indexed: 09/27/2024] Open
Abstract
Despite the increasing number of anti-hypertensive drugs have been developed and used in the clinical setting, persistent deficiencies persist, including issues such as lifelong dosage, combination therapy. Notwithstanding receiving the treatment under enduring these deficiencies, approximately 4 in 5 patients still fail to achieve reliable blood pressure (BP) control. The application of neuromodulation in the context of hypertension presents a pioneering strategy for addressing this condition, con-currently implying a potential central nervous mechanism underlying hypertension onset. We hypothesize that neurological networks, an essential component of maintaining appropriate neurological function, are involved in hypertension. Drawing on both peer-reviewed research and our laboratory investigations, we endeavor to investigate the underlying neural mechanisms involved in hypertension by identifying a close relationship between its onset of hypertension and an excitation and inhibition (E/I) imbalance. In addition to the involvement of excitatory glutamatergic and GABAergic inhibitory system, the pathogenesis of hypertension is also associated with Voltage-gated sodium channels (VGSCs, Nav)-mediated E/I balance. The overloading of glutamate or enhancement of glutamate receptors may be attributed to the E/I imbalance, ultimately triggering hypertension. GABA loss and GABA receptor dysfunction have also proven to be involved. Furthermore, we have identified that abnormalities in sodium channel expression and function alter neural excitability, thereby disturbing E/I balance and potentially serving as a mechanism underlying hypertension. These insights are expected to furnish potential strategies for the advancement of innovative anti-hypertensive therapies and a meaningful reference for the exploration of central nervous system (CNS) targets of anti-hypertensives.
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Affiliation(s)
- Min Xia
- Department of Anesthesiology, General Hospital of The Yangtze River Shipping, Wuhan Brain Hospital, Wuhan, China
- Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, China
| | - Tianyu Wang
- Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, China
| | - Yizhu Wang
- Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, China
- College of Pharmacy, Dalian Medical University, Dalian, China
| | - Tingting Hu
- Department of Anesthesiology, General Hospital of The Yangtze River Shipping, Wuhan Brain Hospital, Wuhan, China
| | - Defang Chen
- Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, China
- Emergency Intensive Care Unit, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bin Wang
- Liaoning Provincial Key Laboratory of Cerebral Diseases, Department of Physiology, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, China
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Zhang S, Zhao D, Yang Z, Wang F, Yang S, Wang C. Circulating mitochondria promoted endothelial cGAS-derived neuroinflammation in subfornical organ to aggravate sympathetic overdrive in heart failure mice. J Neuroinflammation 2024; 21:27. [PMID: 38243316 PMCID: PMC10799549 DOI: 10.1186/s12974-024-03013-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 01/03/2024] [Indexed: 01/21/2024] Open
Abstract
BACKGROUND Sympathoexcitation contributes to myocardial remodeling in heart failure (HF). Increased circulating pro-inflammatory mediators directly act on the Subfornical organ (SFO), the cardiovascular autonomic center, to increase sympathetic outflow. Circulating mitochondria (C-Mito) are the novel discovered mediators for inter-organ communication. Cyclic GMP-AMP synthase (cGAS) is the pro-inflammatory sensor of damaged mitochondria. OBJECTIVES This study aimed to assess the sympathoexcitation effect of C-Mito in HF mice via promoting endothelial cGAS-derived neuroinflammation in the SFO. METHODS C-Mito were isolated from HF mice established by isoprenaline (0.0125 mg/kg) infusion via osmotic mini-pumps for 2 weeks. Structural and functional analyses of C-Mito were conducted. Pre-stained C-Mito were intravenously injected every day for 2 weeks. Specific cGAS knockdown (cGAS KD) in the SFO endothelial cells (ECs) was achieved via the administration of AAV9-TIE-shRNA (cGAS) into the SFO. The activation of cGAS in the SFO ECs was assessed. The expression of the mitochondrial redox regulator Dihydroorotate dehydrogenase (DHODH) and its interaction with cGAS were also explored. Neuroinflammation and neuronal activation in the SFO were evaluated. Sympathetic activity, myocardial remodeling, and cardiac systolic dysfunction were measured. RESULTS C-Mito were successfully isolated, which showed typical structural characteristics of mitochondria with double-membrane and inner crista. Further analysis showed impaired respiratory complexes activities of C-Mito from HF mice (C-MitoHF) accompanied by oxidative damage. C-Mito entered ECs, instead of glial cells and neurons in the SFO of HF mice. C-MitoHF increased the level of ROS and cytosolic free double-strand DNA (dsDNA), and activated cGAS in cultured brain endothelial cells. Furthermore, C-MitoHF highly expressed DHODH, which interacted with cGAS to facilitate endothelial cGAS activation. C-MitoHF aggravated endothelial inflammation, microglial/astroglial activation, and neuronal sensitization in the SFO of HF mice, which could be ameliorated by cGAS KD in the ECs of the SFO. Further analysis showed C-MitoHF failed to exacerbate sympathoexcitation and myocardial sympathetic hyperinnervation in cGAS KD HF mice. C-MitoHF promoted myocardial fibrosis and hypertrophy, and cardiac systolic dysfunction in HF mice, which could be ameliorated by cGAS KD. CONCLUSION Collectively, we demonstrated that damaged C-MitoHF highly expressed DHODH, which promoted endothelial cGAS activation in the SFO, hence aggravating the sympathoexcitation and myocardial injury in HF mice, suggesting that C-Mito might be the novel therapeutic target for sympathoexcitation in HF.
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Affiliation(s)
- Shutian Zhang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
| | - Dajun Zhao
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
| | - Zhaohua Yang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
| | - Fanshun Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China
| | - Shouguo Yang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China.
| | - Chunsheng Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China.
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Liu X, Du H, Pan Y, Li X. New insights into the effect of VMP1 on the treatment of pressure overload-induced pathological cardiac hypertrophy: Involving SERCA-regulated autophagic flux. Microvasc Res 2023; 150:104572. [PMID: 37353069 DOI: 10.1016/j.mvr.2023.104572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/08/2023] [Accepted: 06/17/2023] [Indexed: 06/25/2023]
Abstract
Pathological cardiac hypertrophy is an adaptive reaction in response to pressure or volume overload. Autophagy is critical for damage caused by pathological cardiac hypertrophy. Vacuole membrane protein 1 (VMP1) is an endoplasmic reticulum (ER) transmembrane protein that is effective in activating autophagy. However, the role of VMP1 in pathological cardiac hypertrophy and its underlying mechanisms remain elusive. This study was designed to explore the potential mechanisms of VMP1 on pressure overload-induced pathological cardiac hypertrophy. In this work, abdominal aorta constriction (AAC) surgery was used to induce pathological cardiac hypertrophy in male C57BL/6 mice. H9C2 cardiomyocytes were treated with phenylephrine stimulation (PE) to induce the hypertrophic response. The in vivo results revealed that mice with AAC surgery caused pathological cardiac hypertrophy as evidenced by improved cardiac function according to multiple echocardiographic parameters. Moreover, elevated VMP1 expression was also observed in mice after AAC surgery. VMP1 knockdown aggravated changes in cardiac structure, cardiac dysfunction, and fibrosis. Meanwhile, VMP1 knockdown suppressed autophagy and endoplasmic reticulum calcium ATPase (SERCA) activity in heart tissues. H9C2 cardiomyocytes with VMP1 overexpression were used to investigate the specific mechanism of VMP1 in pathological cardiac hypertrophy, and VMP1 overexpression increased autophagic flux by upregulating SERCA activity. In conclusion, these findings revealed that VMP1 protected against pressure overload-induced pathological cardiac hypertrophy by inducing SERCA-regulated autophagic flux. Our results provide valuable insights regarding the pathophysiology of pathological cardiac hypertrophy and clues to a novel target for the treatment of pathological cardiac hypertrophy.
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Affiliation(s)
- Xue Liu
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Hongjiao Du
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yilong Pan
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xiaodong Li
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
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9
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Gui H, Chen X, Li L, Zhu L, Jing Q, Nie Y, Zhang X. Psychological distress influences lung cancer: Advances and perspectives on the immune system and immunotherapy. Int Immunopharmacol 2023; 121:110251. [PMID: 37348230 DOI: 10.1016/j.intimp.2023.110251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 04/18/2023] [Accepted: 04/25/2023] [Indexed: 06/24/2023]
Abstract
Lung cancer has the highest incidence rate and mortality worldwide. Moreover, multiple factors may cause heterogeneity in the efficacy of immunotherapy for lung cancer, and preclinical studies have gradually uncovered the promotive effects of psychological distress (PD) on tumor hallmarks. Therefore, treatment targeted at PD may be a vital factor in adjusting and improving immunotherapy for lung cancer. Here, by focusing on the central nervous system, as well as stress-related crucial neurotransmitters and hormones, we highlight the effects of PD on the lung immune system, the lung tumor microenvironment (TME) and immunotherapy, which brings a practicable means and psychosocial perspective to lung cancer treatment.
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Affiliation(s)
- Huan Gui
- Department of Hyperbaric Oxygen, People`s Hospital of Qianxinan Buyi and Miao Minority Autonomous Prefecture, Xingyi 562400, China; School of Medicine, Guizhou University, Guiyang 550025, China
| | - Xulong Chen
- School of Medicine, Guizhou University, Guiyang 550025, China; Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
| | - Linzhao Li
- School of Medicine, Guizhou University, Guiyang 550025, China
| | - Lan Zhu
- School of Medicine, Guizhou University, Guiyang 550025, China
| | - Qianyu Jing
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Yingjie Nie
- School of Medicine, Guizhou University, Guiyang 550025, China; NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China.
| | - Xiangyan Zhang
- School of Medicine, Guizhou University, Guiyang 550025, China; NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China.
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10
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Tong L, Chen G, Liu T, Wang L, Zhang H, Chen F, Zhang S, Du D. IFN-γ deficiency in the rostral ventrolateral medulla contributes to stress-induced hypertension by impairing microglial synaptic engulfment. J Hypertens 2023; 41:1323-1332. [PMID: 37260264 DOI: 10.1097/hjh.0000000000003470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
BACKGROUND Dysfunctional neurons and microglia in the rostral ventrolateral medulla (RVLM) have been implicated in the pathogenesis of stress-induced hypertension (SIH). Functional perturbation of microglial synaptic engulfment can induce aberrant brain circuit activity. IFN-γ is a pleiotropic cytokine that plays a role in regulating neuronal activity. However, existing research on the exploration of the effects of microglia on synapses in the RVLM is lacking, particularly on the function of IFN-γ in microglial synaptic engulfment involved in SIH. METHODS A SIH rat model was established by electric foot shocks combined with noise stimulation. The underlying mechanism of IFN-γ on synaptic density and microglial synaptic engulfment was investigated through in-vivo and in-vitro experiments involving gain of function, immunofluorescence, quantitative real-time PCR, western blot, and morphometric analysis. Furthermore, the function of IFN-γ in neuronal activity, renal sympathetic nerve activity (RSNA), and blood pressure (BP) regulation was determined through in-vivo and in-vitro experiments involving Ca 2+ imaging, immunofluorescence, platinum-iridium electrode recording, ELISA, the femoral artery cannulation test, and the tail-cuff method. RESULTS The BP, heart rate, RSNA, plasma norepinephrine, and the number of c-Fos-positive neurons in SIH rats increased compared with those in control rats. Pre and postsynaptic densities in the RVLM also increased in SIH rats. IFN-γ and CCL2 expression levels were significantly reduced in the RVLM of the SIH group, whose microglia also exhibited an impaired capacity for synapse engulfment. IFN-γ elevation increased CCL2 expression and microglial synaptic engulfment and decreased synaptic density in vivo and in vitro . However, CCL2 inhibition reversed these effects. Moreover, the reduction of neuronal excitability, RSNA, plasma norepinephrine, and BP by IFN-γ was abrogated through CCL2 expression. CONCLUSION IFN-γ deficiency in the RVLM impaired the microglial engulfment of synapses by inhibiting CCL2 expression and increasing synaptic density and neuronal excitability, thereby contributing to SIH progression. Targeting IFN-γ may be considered a potential strategy to combat SIH.
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Affiliation(s)
- Lei Tong
- College of Life Sciences, Shanghai University, Shanghai
| | - Gaojun Chen
- College of Life Sciences, Shanghai University, Shanghai
| | - Tianfeng Liu
- College of Life Sciences, Shanghai University, Shanghai
| | - Linping Wang
- College of Life Sciences, Shanghai University, Shanghai
| | - Haili Zhang
- College of Agriculture and Bioengineering, Heze University, Heze
| | - Fuxue Chen
- College of Life Sciences, Shanghai University, Shanghai
| | - Shuai Zhang
- International Cooperation Laboratory of Molecular Medicine, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou
| | - Dongshu Du
- College of Life Sciences, Shanghai University, Shanghai
- College of Agriculture and Bioengineering, Heze University, Heze
- Shaoxing Institute of Shanghai University, Shaoxing, China
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11
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Wang L, Liu T, Wang X, Tong L, Chen G, Zhou S, Zhang H, Liu H, Lu W, Wang G, Zhang S, Du D. Microglia-derived TNF-α contributes to RVLM neuronal mitochondrial dysfunction via blocking the AMPK-Sirt3 pathway in stress-induced hypertension. J Neuroinflammation 2023; 20:137. [PMID: 37264405 DOI: 10.1186/s12974-023-02818-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 05/26/2023] [Indexed: 06/03/2023] Open
Abstract
BACKGROUND Neuroinflammation in the rostral ventrolateral medulla (RVLM) has been associated with the pathogenesis of stress-induced hypertension (SIH). Neuronal mitochondrial dysfunction is involved in many pathological and physiological processes. However, the impact of neuroinflammation on neuronal mitochondrial homeostasis and the involved signaling pathway in the RVLM during SIH are largely unknown. METHODS The morphology and phenotype of microglia and the neuronal mitochondrial injury in vivo were analyzed by immunofluorescence, Western blot, RT-qPCR, transmission electron microscopy, and kit detection. The underlying mechanisms of microglia-derived tumor necrosis factor-α (TNF-α) on neuronal mitochondrial function were investigated through in vitro and in vivo experiments such as immunofluorescence and Western blot. The effect of TNF-α on blood pressure (BP) regulation was determined in vivo via intra-RVLM microinjection of TNF-α receptor antagonist R7050. RESULTS The results demonstrated that BP, heart rate (HR), renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE), and electroencephalogram (EEG) power increased in SIH rats. Furthermore, the branching complexity of microglia in the RVLM of SIH rats decreased and polarized into M1 phenotype, accompanied by upregulation of TNF-α. Increased neuronal mitochondria injury was observed in the RVLM of SIH rats. Mechanistically, Sirtuin 3 (Sirt3) and p-AMPK expression were markedly downregulated in both SIH rats and TNF-α-treated N2a cells. AMPK activator A769662 upregulated AMPK-Sirt3 signaling pathway and consequently reversed TNF-α-induced mitochondrial dysfunction. Microinjection of TNF-α receptor antagonist R7050 into the RVLM of SIH rats significantly inhibited the biological activities of TNF-α, increased p-AMPK and Sirt3 levels, and alleviated neuronal mitochondrial injury, thereby reducing c-FOS expression, RSNA, plasma NE, and BP. CONCLUSIONS This study revealed that microglia-derived TNF-α in the RVLM impairs neuronal mitochondrial function in SIH possibly through inhibiting the AMPK-Sirt3 pathway. Therefore, microglia-derived TNF-α in the RVLM may be a possible therapeutic target for the intervention of SIH.
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Affiliation(s)
- Linping Wang
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai, China
- College of Life Sciences, Shanghai University, Shanghai, China
| | - Tianfeng Liu
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai, China
- College of Life Sciences, Shanghai University, Shanghai, China
| | - Xueping Wang
- College of Life Sciences, Shanghai University, Shanghai, China
| | - Lei Tong
- College of Life Sciences, Shanghai University, Shanghai, China
| | - Gaojun Chen
- College of Life Sciences, Shanghai University, Shanghai, China
| | - Shumin Zhou
- College of Life Sciences, Shanghai University, Shanghai, China
| | - Haili Zhang
- College of Agriculture and Bioengineering, Heze University, Heze, Shandong, China
| | - Haisheng Liu
- College of Agriculture and Bioengineering, Heze University, Heze, Shandong, China
| | - Wen Lu
- College of Agriculture and Bioengineering, Heze University, Heze, Shandong, China
| | - Guohua Wang
- Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226019, Jiangsu, China
| | - Shuai Zhang
- International Cooperation Laboratory of Molecular Medicine, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
| | - Dongshu Du
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai, China.
- College of Life Sciences, Shanghai University, Shanghai, China.
- College of Agriculture and Bioengineering, Heze University, Heze, Shandong, China.
- Shaoxing Institute of Shanghai University, Shaoxing, Zhejiang, China.
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12
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Liu T, Wang L, Chen G, Tong L, Ye X, Yang H, Liu H, Zhang H, Lu W, Zhang S, Du D. PDZD8-mediated endoplasmic reticulum-mitochondria associations regulate sympathetic drive and blood pressure through the intervention of neuronal mitochondrial homeostasis in stress-induced hypertension. Neurobiol Dis 2023:106173. [PMID: 37247681 DOI: 10.1016/j.nbd.2023.106173] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 05/31/2023] Open
Abstract
Neuronal hyperexcitation in the rostral ventrolateral medulla (RVLM) drives heightened sympathetic nerve activity and contributes to the etiology of stress-induced hypertension (SIH). Maintenance of mitochondrial functions is central to neuronal homeostasis. PDZD8, an endoplasmic reticulum (ER) transmembrane protein, tethers ER to mitochondria. However, the mechanisms of PDZD8-mediated ER-mitochondria associations regulating neuronal mitochondrial functions and thereby mediating blood pressure (BP) in the RVLM of SIH were largely unknown. SIH rats were subjected to intermittent electric foot shocks plus noise for 2 h twice daily for 15 consecutive days. The underlying mechanisms of PDZD8 were investigated through in vitro experiments by using small interfering RNA and through in vivo experiments, such as intra-RVLM microinjection and Western blot analysis. The function of PDZD8 on BP regulation in the RVLM was determined in vivo via the intra-RVLM microinjection of adeno-associated virus (AAV)2-r-Pdzd8. We found that the c-Fos-positive RVLM tyrosine hydroxylase (TH) neurons, renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE) level, BP, and heart rate (HR) were elevated in SIH rats. ER-mitochondria associations in RVLM neurons were significantly reduced in SIH rats. PDZD8 was mainly expressed in RVLM neurons, and mRNA and protein levels were markedly decreased in SIH rats. In N2a cells, PDZD8 knockdown disrupted ER-mitochondria associations and mitochondrial structure, decreased mitochondrial membrane potential (MMP) and respiratory metabolism, enhanced ROS levels, and reduced catalase (CAT) activity. These effects suggested that PDZD8 dysregulation induced mitochondrial malfunction. By contrast, PDZD8 upregulation in the RVLM of SIH rats could rescue neuronal mitochondrial function, thereby suppressing c-Fos expression in TH neurons and decreasing RSNA, plasma NE, BP, and HR. Our results indicated that the dysregulation of PDZD8-mediated ER-mitochondria associations led to the loss of the activity homeostasis of RVLM neurons by disrupting mitochondrial functions, thereby participating in the regulation of SIH pathology.
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Affiliation(s)
- Tianfeng Liu
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China; College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Linping Wang
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China; College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Gaojun Chen
- College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Lei Tong
- College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Xuanxuan Ye
- College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Hui Yang
- College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Haisheng Liu
- College of Agriculture and Bioengineering, Heze University, Heze 274000, China
| | - Haili Zhang
- College of Agriculture and Bioengineering, Heze University, Heze 274000, China
| | - Wen Lu
- College of Agriculture and Bioengineering, Heze University, Heze 274000, China
| | - Shuai Zhang
- International Cooperation Laboratory of Molecular Medicine, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
| | - Dongshu Du
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China; College of Life Sciences, Shanghai University, Shanghai 200444, China; Shaoxing Institute of Shanghai University, Shaoxing, Zhejiang 312000, China; College of Agriculture and Bioengineering, Heze University, Heze 274000, China.
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13
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Han C, Qian X, Ren X, Zhang S, Hu L, Li J, Huang Y, Huang R, Ooi K, Lin H, Xia C. Inhibition of cGAS in Paraventricular Nucleus Attenuates Hypertensive Heart Injury Via Regulating Microglial Autophagy. Mol Neurobiol 2022; 59:7006-7024. [PMID: 36070120 PMCID: PMC9450841 DOI: 10.1007/s12035-022-02994-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 08/07/2022] [Indexed: 11/30/2022]
Abstract
Neuroinflammation in the cardiovascular center plays a critical role in the progression of hypertensive heart disease. And microglial autophagy is involved in the regulation of neuroinflammation. Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, senses mitochondrial DNA (mtDNA) and regulates autophagy. The detailed mechanisms of central cGAS affects neuroinflammatory response in hypertensive heart disease via regulating autophagy remain unknown. Angiotensin II (Ang II, 1.5 mg·kg−1·12 h−1, 2 weeks) was intraperitoneally injected to induce hypertension in mice. The cGAS-STING pathway was activated in the paraventricular nucleus (PVN) of Ang II-induced hypertensive mice. The contractile dysfunction of heart was alleviated in Ang II-induced hypertensive cGAS−/− mice. To observe the central effects of cGAS on regulating hypertensive heart disease, the RU.521 (a cGAS inhibitor) was intracisternally infused in hypertensive mice. Intracisternal infusion of the RU.521-alleviated myocardial interstitial fibrosis, cardiomyocyte hypertrophy, and the contractile dysfunction in Ang II-induced hypertensive mice. Intracisternal infusion of RU.521 attenuated the microglial activation, neuroinflammation, sympathetic/parasympathetic activity ratio, and lowered blood pressure. The autophagic flux in the PVN cells was blocked, while intracisternal infusion of RU.521 alleviated this effect in the Ang II-induced hypertensive mice. In vitro, it was found that cGAS-STING activation-induced autophagic flux blockage, while when the impaired autophagic flux was facilitated by rapamycin, an autophagy inducer, the microglial M1 polarization was decreased correspondingly. In conclusion, cGAS induces the inflammatory phenotype of microglia via impairing autophagic flux, thereby participating in neuroinflammation, which leads to sympathetic overactivation in hypertension and further caused hypertensive myocardial injury.
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Affiliation(s)
- Chengzhi Han
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.,Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xinyi Qian
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.,Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xiaorong Ren
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.,Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Shutian Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.,Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Li Hu
- Department of Cardiovascular Diseases, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jingyao Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Yijun Huang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.,Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Renhui Huang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.,Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Kokwin Ooi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Hong Lin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.,Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Chunmei Xia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.
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14
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Yu XJ, Liu XJ, Guo J, Su YK, Zhang N, Qi J, Li Y, Fu LY, Liu KL, Li Y, Kang YM. Blockade of Microglial Activation in Hypothalamic Paraventricular Nucleus Improves High Salt-Induced Hypertension. Am J Hypertens 2022; 35:820-827. [PMID: 35439285 DOI: 10.1093/ajh/hpac052] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 02/07/2022] [Accepted: 04/17/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND It has been shown that activated microglia in brain releasing proinflammatory cytokines (PICs) contribute to the progression of cardiovascular diseases. In this study, we tested the hypothesis that microglial activation in hypothalamic paraventricular nucleus (PVN), induced by high-salt diet, increases the oxidative stress via releasing PICs and promotes sympathoexcitation and development of hypertension. METHODS High-salt diet was given to male Dahl salt-sensitive rats to induce hypertension. Those rats were bilaterally implanted with cannula for PVN infusion of minocycline, a selective microglial activation blocker, or artificial cerebrospinal fluid for 4 weeks. RESULTS High-salt diet elevated mean arterial pressure of Dahl salt-sensitive rats. Meanwhile, elevations of renal sympathetic nerve activity and central prostaglandin E2, as well as increase of plasma norepinephrine, were observed in those hypertensive rats. Tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6 increased in the PVN of those rats, associated with a significant activation of microglia and prominent disruption of redox balance, which was demonstrated by higher superoxide and NAD(P)H oxidase 2 (NOX-2) and NAD(P)H oxidase 4 (NOX-4), and lower Cu/Zn superoxide dismutase in PVN. PVN infusion of minocycline attenuated all hypertension-related alterations described above. CONCLUSION This study indicates that high salt leads to microglial activation within PVN of hypertensive rats, and those activated PVN microglia release PICs and trigger the production of reactive oxygen species, which contributes to sympathoexcitation and development of hypertension. Blockade of PVN microglial activation inhibits inflammation and oxidative stress, therefore attenuating the development of hypertension induced by high-salt diet.
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Affiliation(s)
- Xiao-Jing Yu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, China
| | - Xiao-Jing Liu
- Department of Cardiology, The Second Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Jing Guo
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, China
| | - Yu-Kun Su
- Hemodialysis Center, Shanxi Second People's Hospital, Taiyuan, China
| | - Nianping Zhang
- Department of Clinical Medicine, Shanxi Datong University School of Medicine, Datong, China
| | - Jie Qi
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, China
| | - Ying Li
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, China
| | - Li-Yan Fu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, China
| | - Kai-Li Liu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, China
| | - Yanjun Li
- Department of Microbiology and Immunology, Shanxi Datong University School of Medicine, Datong, China
| | - Yu-Ming Kang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, China
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15
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Li P, Luo X, Luo Z, He GL, Shen TT, Yu XT, Wang ZZ, Tan YL, Liu XQ, Yang XS. Increased miR-155 in Microglial Exosomes Following Heat Stress Accelerates Neuronal Autophagy via Their Transfer Into Neurons. Front Cell Neurosci 2022; 16:865568. [PMID: 35634460 PMCID: PMC9132214 DOI: 10.3389/fncel.2022.865568] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 04/25/2022] [Indexed: 12/21/2022] Open
Abstract
Background Heat stroke is the outcome of excessive heat stress, which results in core temperatures exceeding 40°C accompanied by a series of complications. The brain is particularly vulnerable to damage from heat stress. In our previous studies, both activated microglia and increased neuronal autophagy were found in the cortices of mice with heat stroke. However, whether activated microglia can accelerate neuronal autophagy under heat stress conditions is still unknown. In this study, we aimed to investigate the underlying mechanism that caused neuronal autophagy upregulation in heat stroke from the perspective of exosome-mediated intercellular communication. Methods In this study, BV2 and N2a cells were used instead of microglia and neurons, respectively. Exosomes were extracted from BV2 culture supernatants by ultracentrifugation and then characterized via transmission electron microscopy, nanoparticle tracking analysis and Western blotting. N2a cells pretreated with/without miR-155 inhibitor were cocultured with microglial exosomes that were treated with/without heat stress or miR-155 overexpression and subsequently subjected to heat stress treatment. Autophagy in N2a cells was assessed by detecting autophagosomes and autophagy-related proteins through transmission electron microscopy, immunofluorescence, and Western blotting. The expression of miR-155 in BV2 and BV2 exosomes and N2a cells was measured using real-time reverse transcription polymerase chain reaction. Target binding analysis was verified via a dual-luciferase reporter assay. Results N2a autophagy moderately increased in response to heat stress and accelerated by BV2 cells through transferring exosomes to neurons. Furthermore, we found that neuronal autophagy was positively correlated with the content of miR-155 in microglial exosomes. Inhibition of miR-155 partly abolished autophagy in N2a cells, which was increased by coculture with miR-155-upregulated exosomes. Mechanistic analysis confirmed that Rheb is a functional target of miR-155 and that microglial exosomal miR-155 accelerated heat stress-induced neuronal autophagy mainly by regulating the Rheb-mTOR signaling pathway. Conclusion Increased miR-155 in microglial exosomes after heat stroke can induce neuronal autophagy via their transfer into neurons. miR-155 exerted these effects by targeting Rheb, thus inhibiting the activity of mTOR signaling. Therefore, miR-155 could be a promising target for interventions of neuronal autophagy after heat stroke.
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Affiliation(s)
- Ping Li
- Department of Tropical Medicine, Army Medical University, Chongqing, China
- Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Army Medical University, Chongqing, China
| | - Xue Luo
- Department of Tropical Medicine, Army Medical University, Chongqing, China
| | - Zhen Luo
- Department of Tropical Medicine, Army Medical University, Chongqing, China
| | - Gen-Lin He
- Department of Tropical Medicine, Army Medical University, Chongqing, China
| | - Ting-Ting Shen
- Department of Tropical Medicine, Army Medical University, Chongqing, China
| | - Xue-Ting Yu
- Department of Tropical Medicine, Army Medical University, Chongqing, China
| | - Ze-Ze Wang
- Department of Tropical Medicine, Army Medical University, Chongqing, China
| | - Yu-Long Tan
- Department of Tropical Medicine, Army Medical University, Chongqing, China
| | - Xiao-Qian Liu
- Department of Tropical Medicine, Army Medical University, Chongqing, China
| | - Xue-Sen Yang
- Department of Tropical Medicine, Army Medical University, Chongqing, China
- Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Army Medical University, Chongqing, China
- *Correspondence: Xue-Sen Yang,
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16
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Zhang S, Xing M, Chen G, Tong L, Zhang H, Du D. Upregulation of miR‐335 and miR‐674‐3p in the rostral ventrolateral medulla contributes to stress‐induced hypertension. J Neurochem 2022; 161:387-404. [DOI: 10.1111/jnc.15589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/05/2022] [Accepted: 02/07/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Shuai Zhang
- International Cooperation Laboratory of Molecular Medicine, Academy of Chinese Medical Sciences Zhejiang Chinese Medical University Hangzhou Zhejiang China
| | - Mengyu Xing
- Shanghai Key Laboratory of Bio‐Energy Crops, School of Life Sciences Shanghai University Shanghai China
- School of Life Scicences Shanghai University Shanghai China
| | - Gaojun Chen
- Shanghai Key Laboratory of Bio‐Energy Crops, School of Life Sciences Shanghai University Shanghai China
- School of Life Scicences Shanghai University Shanghai China
| | - Lei Tong
- Shanghai Key Laboratory of Bio‐Energy Crops, School of Life Sciences Shanghai University Shanghai China
- School of Life Scicences Shanghai University Shanghai China
| | - Haili Zhang
- School of Life Sciences Heze University Heze Shandong China
| | - Dongshu Du
- Shanghai Key Laboratory of Bio‐Energy Crops, School of Life Sciences Shanghai University Shanghai China
- School of Life Scicences Shanghai University Shanghai China
- Shaoxing institute of technology Zhejiang China
- School of Life Sciences Heze University Heze Shandong China
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17
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Zhang S, Hu L, Han C, Huang R, Ooi K, Qian X, Ren X, Chu D, Zhang H, Du D, Xia C. PLIN2 Mediates Neuroinflammation and Oxidative/Nitrosative Stress via Downregulating Phosphatidylethanolamine in the Rostral Ventrolateral Medulla of Stressed Hypertensive Rats. J Inflamm Res 2021; 14:6331-6348. [PMID: 34880641 PMCID: PMC8646230 DOI: 10.2147/jir.s329230] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/03/2021] [Indexed: 12/22/2022] Open
Abstract
Purpose Oxidative/nitrosative stress, neuroinflammation and their intimate interactions mediate sympathetic overactivation in hypertension. An immoderate inflammatory response is characterized not only by elevated proinflammatory cytokines (PICs) but by increases in mitochondrial dysfunction, reactive oxygen species (ROS), and nitric oxide (NO). Recent data pinpoint that both the phospholipid and lipid droplets (LDs) are potent modulators of microglia physiology. Methods Stress rats underwent compound stressors for 15 days with PLIN2-siRNA or scrambled-siRNA (SC-siRNA) administrated into the rostral ventrolateral medulla (RVLM). Lipids were analyzed by mass spectroscopy-based quantitative lipidomics. The phenotypes and proliferation of microglia, LDs, in the RVLM of rats were detected; blood pressure (BP) and myocardial injury in rats were evaluated. The anti-oxidative/nitrosative stress effect of phosphatidylethanolamine (PE) was explored in cultured primary microglia. Results Lipidomics analysis showed that 75 individual lipids in RVLM were significantly dysregulated by stress [PE was the most one], demonstrating that lipid composition changed with stress. In vitro, prorenin stress induced the accumulation of LDs, increased PICs, which could be blocked by siRNA-PLIN2 in microglia. PLIN2 knockdown upregulated the PE synthesis in microglia. Anti-oxidative/nitrosative stress effect of PE delivery was confirmed by the decrease of ROS and decrease in 3-NT and MDA in prorenin-treated microglia. PLIN2 knockdown in the RVLM blocked the number of iNOS+ and PCNA+ microglia, decreased BP, alleviated cardiac fibrosis and hypertrophy in stressed rats. Conclusion PLIN2 mediates microglial polarization/proliferation via downregulating PE in the RVLM of stressed rats. Delivery of PE is a promising strategy for combating neuroinflammation and oxidative/nitrosative stress in stress-induced hypertension.
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Affiliation(s)
- Shutian Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Li Hu
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200240, People's Republic of China
| | - Chengzhi Han
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Renhui Huang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Kokwin Ooi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xinyi Qian
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xiaorong Ren
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Dechang Chu
- College of Agriculture and Bioengineering, Heze University, Heze, 274000, People's Republic of China
| | - Haili Zhang
- College of Agriculture and Bioengineering, Heze University, Heze, 274000, People's Republic of China
| | - Dongshu Du
- School of Life Science, Shanghai University, Shanghai, 200444, People's Republic of China
| | - Chunmei Xia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
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18
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Ooi K, Hu L, Feng Y, Han C, Ren X, Qian X, Huang H, Chen S, Shi Q, Lin H, Wang J, Zhu D, Wang R, Xia C. Sigma-1 Receptor Activation Suppresses Microglia M1 Polarization via Regulating Endoplasmic Reticulum-Mitochondria Contact and Mitochondrial Functions in Stress-Induced Hypertension Rats. Mol Neurobiol 2021; 58:6625-6646. [PMID: 34601668 DOI: 10.1007/s12035-021-02488-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 07/08/2021] [Indexed: 12/31/2022]
Abstract
Exposure to stress plays a detrimental role in the pathogenesis of hypertension via neuroinflammation pathways. Microglial neuroinflammation in the rostral ventrolateral medulla (RVLM) exacerbates stress-induced hypertension (SIH) by increasing sympathetic hyperactivity. Mitochondria of microglia are the regulators of innate immune response. Sigma-1R (σ-1R) localizes to the mitochondria-associated membranes (MAMs) and regulates endoplasmic reticulum (ER) and mitochondria communication, in part through its chaperone activity. The present study aims to investigate the protective role of σ-1R on microglial-mediated neuroinflammation. Stress-induced hypertension (SIH) was induced in rats using electric foot shocks and intermittent noise. Arterial blood pressure (ABP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were measured to evaluate the sympathetic nervous system (SNS) activities. SKF10047 (100 µM), an agonist of σ-1R, was administrated to rats, then σ-1R localization and MAM alterations were detected by immuno-electron microscopy. Mitochondrial calcium homeostasis was examined in primary microglia and/or BV-2 microglia cells. The effect of SKF10047 treatment on the mitochondrial respiratory function of cultured microglia was measured using a Seahorse Extracellular Flux Analyzer. Confocal microscopic images were performed to indicate mitochondrial dynamics. Stress reduces σ-1R's localization at the MAMs, leading to decreased ER-mitochondria contact and IP3R-GRP75-VDAC calcium transport complexes expression in the RVLM of rats. SKF10047 promotes the length and coverage of MAMs in the prorenin-treated microglia. Prorenin treatment increases mitoROS levels, and inhibits Ca2+ signalling between the two organelles, therefore negatively affects ATP production in BV2 cells, and these effects are reversed by SKF10047 treatment. We found mitochondrial hyperfusion and microglial M1 polarization in prorenin-treated microglia. SKF10047 suppresses microglial M1 polarization and RVLM neuroinflammation, subsequently ameliorates sympathetic hyperactivity in stress-induced hypertensive rats. Sigma-1 receptor activation suppresses microglia M1 polarization and neuroinflammation via regulating endoplasmic reticulum-mitochondria contact and mitochondrial functions in stress-induced hypertension rats.
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Affiliation(s)
- Kokwin Ooi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Li Hu
- Department of Cardiovascular Diseases, Renji Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yi Feng
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Chenzhi Han
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Xiaorong Ren
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Xinyi Qian
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Haofeng Huang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Sijia Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Qi Shi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Hong Lin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Jijiang Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Danian Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Rui Wang
- Department of Cardiovascular Diseases, Yangpu District Central Hospital Affiliated to Tongji University School of Medicine, Shanghai, 200090, People's Republic of China.
| | - Chunmei Xia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China.
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19
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Limanaqi F, Busceti CL, Celli R, Biagioni F, Fornai F. Autophagy as a gateway for the effects of methamphetamine: From neurotransmitter release and synaptic plasticity to psychiatric and neurodegenerative disorders. Prog Neurobiol 2021; 204:102112. [PMID: 34171442 DOI: 10.1016/j.pneurobio.2021.102112] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 02/27/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
As a major eukaryotic cell clearing machinery, autophagy grants cell proteostasis, which is key for neurotransmitter release, synaptic plasticity, and neuronal survival. In line with this, besides neuropathological events, autophagy dysfunctions are bound to synaptic alterations that occur in mental disorders, and early on, in neurodegenerative diseases. This is also the case of methamphetamine (METH) abuse, which leads to psychiatric disturbances and neurotoxicity. While consistently altering the autophagy machinery, METH produces behavioral and neurotoxic effects through molecular and biochemical events that can be recapitulated by autophagy blockade. These consist of altered physiological dopamine (DA) release, abnormal stimulation of DA and glutamate receptors, as well as oxidative, excitotoxic, and neuroinflammatory events. Recent molecular insights suggest that METH early impairs the autophagy machinery, though its functional significance remains to be investigated. Here we discuss evidence suggesting that alterations of DA transmission and autophagy are intermingled within a chain of events underlying behavioral alterations and neurodegenerative phenomena produced by METH. Understanding how METH alters the autophagy machinery is expected to provide novel insights into the neurobiology of METH addiction sharing some features with psychiatric disorders and parkinsonism.
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Affiliation(s)
- Fiona Limanaqi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma, 55, 56126, Pisa, PI, Italy
| | | | - Roberta Celli
- IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli, IS, Italy
| | | | - Francesco Fornai
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma, 55, 56126, Pisa, PI, Italy; IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli, IS, Italy.
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20
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Paraventricular Nucleus P2X7 Receptors Aggravate Acute Myocardial Infarction Injury via ROS-Induced Vasopressin-V1b Activation in Rats. Neurosci Bull 2021; 37:641-656. [PMID: 33620697 PMCID: PMC8099953 DOI: 10.1007/s12264-021-00641-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 09/16/2020] [Indexed: 12/27/2022] Open
Abstract
The present study was designed to investigate the mechanisms by which P2X7 receptors (P2X7Rs) mediate the activation of vasopressinergic neurons thereby increasing sympathetic hyperactivity in the paraventricular nucleus (PVN) of the hypothalamus of rats with acute myocardial ischemia (AMI). The left anterior descending branch of the coronary artery was ligated to induce AMI in rats. The rats were pretreated with BBG (brilliant blue G, a P2X7R antagonist), nelivaptan (a vasopressin V1b receptor antagonist), or diphenyleneiodonium (DPI) [an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor]. Hemodynamic parameters of the heart were monitored. Myocardial injury and cardiomyocyte apoptosis were assessed. In the PVN of AMI rats, P2X7R mediated microglial activation, while reactive oxygen species (ROS) and NADPH oxidase 2 (NOX2) were higher than in the sham group. Intraperitoneal injection of BBG effectively reduced ROS production and vasopressin expression in the PVN of AMI rats. Moreover, both BBG and DPI pretreatment effectively reduced sympathetic hyperactivity and ameliorated AMI injury, as represented by reduced inflammation and apoptosis of cardiomyocytes. Furthermore, microinjection of nelivaptan into the PVN improved cardiac function and reduced the norepinephrine (AE) levels in AMI rats. Collectively, the results suggest that, within the PVN of AMI rats, P2X7R upregulation mediates microglial activation and the overproduction of ROS, which in turn activates vasopressinergic neuron-V1b receptors and sympathetic hyperactivity, hence aggravating myocardial injury in the AMI setting.
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21
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Fatoba O, Itokazu T, Yamashita T. Complement cascade functions during brain development and neurodegeneration. FEBS J 2021; 289:2085-2109. [PMID: 33599083 DOI: 10.1111/febs.15772] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 02/07/2021] [Accepted: 02/16/2021] [Indexed: 12/12/2022]
Abstract
The complement system, an essential tightly regulated innate immune system, is a key regulator of normal central nervous system (CNS) development and function. However, aberrant complement component expression and activation in the brain may culminate into marked neuroinflammatory response, neurodegenerative processes and cognitive impairment. Over the years, complement-mediated neuroinflammatory responses and complement-driven neurodegeneration have been increasingly implicated in the pathogenesis of a wide spectrum of CNS disorders. This review describes how complement system contributes to normal brain development and function. We also discuss how pathologic insults such as misfolded proteins, lipid droplet/lipid droplet-associated protein or glycosaminoglycan accumulation could trigger complement-mediated neuroinflammatory responses and neurodegenerative process in neurodegenerative proteinopathies, age-related macular degeneration and neurodegenerative lysosomal storage disorders.
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Affiliation(s)
- Oluwaseun Fatoba
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.,WPI-Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Takahide Itokazu
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.,Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Toshihide Yamashita
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.,WPI-Immunology Frontier Research Center, Osaka University, Suita, Japan.,Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, Suita, Japan
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22
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Huang S, Liu H, Lin Y, Liu M, Li Y, Mao H, Zhang Z, Zhang Y, Ye P, Ding L, Zhu Z, Yang X, Chen C, Zhu X, Huang X, Guo W, Xu P, Lu L. Berberine Protects Against NLRP3 Inflammasome via Ameliorating Autophagic Impairment in MPTP-Induced Parkinson's Disease Model. Front Pharmacol 2021; 11:618787. [PMID: 33584302 PMCID: PMC7872967 DOI: 10.3389/fphar.2020.618787] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 12/30/2020] [Indexed: 12/17/2022] Open
Abstract
The NLR family pyrin domain containing 3 (NLRP3) inflammasome was reported to be regulated by autophagy and activated during inflammatory procession of Parkinson’s disease (PD). Berberine (BBR) is well-studied to play an important role in promoting anti-inflammatory response to mediate the autophagy activity. However, the effect of Berberine on NLRP3 inflammasome in PD and its potential mechanisms remain unclear. Hence, in this study, we investigated the effects of BBR on 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, by evaluating their behavioral changes, dopaminergic (DA) neurons loss, neuroinflammation, NLRP3 inflammasome and autophagic activity. BBR was also applied in BV2 cells treated with 1-methyl-4-pehnyl-pyridine (MPP+). The autophagy inhibitor 3-Methyladenine (3-MA) was administrated to block autophagy activity both in vivo and in vitro. In our in vivo studies, compared to MPTP group, mice in MPTP + BBR group showed significant amelioration of behavioral disorders, mitigation of neurotoxicity and NLRP3-associated neuroinflammation, enhancement of the autophagic process in substantia nigra (SN). In vitro, compared to MPP+ group, BBR significantly decreased the level of NLRP3 inflammasome including the expressions of NLRP3, PYD and CARD domain containing (PYCARD), cleaved caspase 1 (CASP1), and mature interleukin 1 beta (IL1B), via enhancing autophagic activity. Furthermore, BBR treatment increased the formation of autophagosomes in MPP+-treated BV2 cells. Taken together, our data indicated that BBR prevents NLRP3 inflammasome activation and restores autophagic activity to protect DA neurons against degeneration in vivo and in vitro, suggesting that BBR may be a potential therapeutic to treat PD.
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Affiliation(s)
- Shuxuan Huang
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Neurology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Hanqun Liu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuwan Lin
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Muchang Liu
- Department of Medical Affair, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yanhua Li
- Department of Neurology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Hengxu Mao
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhiling Zhang
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yunlong Zhang
- Department of Neuroscience, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Panghai Ye
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Liuyan Ding
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ziting Zhu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xinling Yang
- Department of Neurology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Chaojun Chen
- Department of Neurology, Guangzhou Chinese Medical Integrated Hospital (Huadu), Guangzhou, China
| | - Xiaoqin Zhu
- Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Xiaoyun Huang
- Department of Neurology, The affiliated Houjie Hospital, Guangdong Medical University, Dongguan, China
| | - Wenyuan Guo
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Pingyi Xu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lin Lu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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23
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Autophagy status as a gateway for stress-induced catecholamine interplay in neurodegeneration. Neurosci Biobehav Rev 2021; 123:238-256. [PMID: 33497785 DOI: 10.1016/j.neubiorev.2021.01.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 01/08/2021] [Accepted: 01/09/2021] [Indexed: 12/13/2022]
Abstract
The catecholamine-containing brainstem nuclei locus coeruleus (LC) and ventral tegmental area (VTA) are critically involved in stress responses. Alterations of catecholamine systems during chronic stress may contribute to neurodegeneration, including cognitive decline. Stress-related catecholamine alterations, while contributing to anxiety and depression, might accelerate neuronal degeneration by increasing the formation of toxic dopamine and norepinephrine by-products. These, in turn, may impair proteostasis within a variety of cortical and subcortical areas. In particular, the molecular events governing neurotransmission, neuroplasticity, and proteostasis within LC and VTA affect a variety of brain areas. Therefore, we focus on alterations of autophagy machinery in these nuclei as a relevant trigger in this chain of events. In fact, these catecholamine-containing areas are mostly prone to autophagy-dependent neurodegeneration. Thus, we propose a dynamic hypothesis according to which stress-induced autophagy alterations within the LC-VTA network foster a cascade towards early neurodegeneration within these nuclei.
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24
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Pinnell JR, Cui M, Tieu K. Exosomes in Parkinson disease. J Neurochem 2021; 157:413-428. [PMID: 33372290 DOI: 10.1111/jnc.15288] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/17/2020] [Accepted: 12/23/2020] [Indexed: 12/18/2022]
Abstract
Parkinson disease (PD) is a prevalent neurodegenerative disease, in which the formation of misfolded and aggregated α-synuclein is a key neuropathological hallmark. Recent studies reveal that extracellular vesicles such as exosomes present a potential mechanism for propagation of pathological α-synuclein throughout the brain. The ability of exosomes to transport proteins and genetic material between cells, including mRNA and microRNAs which have been implicated in PD pathology, provides critical insights as to how exosomes may contribute to pathological progression in PD. Advances have also been made in the investigation of exosomes as potential tools for the modulation of Parkinson's pathology; their detection extracellularly may facilitate their use as biomarkers, while their small size could be utilised as vectors for the delivery of therapeutics. The aim of this review was to highlight our current knowledge of the role of exosomes in PD and potential clinical application.
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Affiliation(s)
- Jennifer R Pinnell
- Department of Environmental Health Sciences, Florida International University, Miami, FL, USA.,Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth, UK
| | - Mei Cui
- Department of Neurology, Huashan hospital, Fudan University, Shanghai, China
| | - Kim Tieu
- Department of Environmental Health Sciences, Florida International University, Miami, FL, USA.,Biomolecular Sciences Institute, Florida International University, Miami, FL, USA
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25
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Wu AG, Zhou XG, Qiao G, Yu L, Tang Y, Yan L, Qiu WQ, Pan R, Yu CL, Law BYK, Qin DL, Wu JM. Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases. Ageing Res Rev 2021; 65:101202. [PMID: 33161129 DOI: 10.1016/j.arr.2020.101202] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023]
Abstract
Neuroinflammation is considered as a detrimental factor in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), etc. Nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3), the most well-studied inflammasome, is abundantly expressed in microglia and has gained considerable attention. Misfolded proteins are characterized as the common hallmarks of neurodegenerative diseases due to not only their induced neuronal toxicity but also their effects in over-activating microglia and the NLRP3 inflammasome. The activated NLRP3 inflammasome aggravates the pathology and accelerates the progression of neurodegenerative diseases. Emerging evidence indicates that microglial autophagy plays an important role in the maintenance of brain homeostasis and the negative regulation of NLRP3 inflammasome-mediated neuroinflammation. The excessive activation of NLRP3 inflammasome impairs microglial autophagy and further aggravates the pathogenesis of neurodegenerative diseases. In this review article, we summarize and discuss the NLRP3 inflammasome and its specific inhibitors in microglia. The crucial role of microglial autophagy and its inducers in the removal of misfolded proteins, the clearance of damaged mitochondria and reactive oxygen species (ROS), and the degradation of the NLRP3 inflammasome or its components in neurodegenerative diseases are summarized. Understanding the underlying mechanisms behind the sex differences in NLRP3 inflammasome-mediated neurodegenerative diseases will help researchers to develop more targeted therapies and increase our diagnostic and prognostic abilities. In addition, the superiority of the combined use of microglial autophagy inducers with the specific inhibitors of the NLRP3 inflammasome in the inhibition of NLRP3 inflammasome-mediated neuroinflammation requires further preclinical and clinical validations in the future.
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26
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Guo M, Wang J, Zhao Y, Feng Y, Han S, Dong Q, Cui M, Tieu K. Microglial exosomes facilitate α-synuclein transmission in Parkinson's disease. Brain 2020; 143:1476-1497. [PMID: 32355963 DOI: 10.1093/brain/awaa090] [Citation(s) in RCA: 336] [Impact Index Per Article: 67.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 01/08/2020] [Accepted: 03/15/2020] [Indexed: 12/14/2022] Open
Abstract
Accumulation of neuronal α-synuclein is a prominent feature in Parkinson's disease. More recently, such abnormal protein aggregation has been reported to spread from cell to cell and exosomes are considered as important mediators. The focus of such research, however, has been primarily in neurons. Given the increasing recognition of the importance of non-cell autonomous-mediated neurotoxicity, it is critical to investigate the contribution of glia to α-synuclein aggregation and spread. Microglia are the primary phagocytes in the brain and have been well-documented as inducers of neuroinflammation. How and to what extent microglia and their exosomes impact α-synuclein pathology has not been well delineated. We report here that when treated with human α-synuclein preformed fibrils, exosomes containing α-synuclein released by microglia are fully capable of inducing protein aggregation in the recipient neurons. Additionally, when combined with microglial proinflammatory cytokines, these exosomes further increased protein aggregation in neurons. Inhibition of exosome synthesis in microglia reduced α-synuclein transmission. The in vivo significance of these exosomes was demonstrated by stereotaxic injection of exosomes isolated from α-synuclein preformed fibrils treated microglia into the mouse striatum. Phosphorylated α-synuclein was observed in multiple brain regions consistent with their neuronal connectivity. These animals also exhibited neurodegeneration in the nigrostriatal pathway in a time-dependent manner. Depleting microglia in vivo dramatically suppressed the transmission of α-synuclein after stereotaxic injection of preformed fibrils. Mechanistically, we report here that α-synuclein preformed fibrils impaired autophagy flux by upregulating PELI1, which in turn, resulted in degradation of LAMP2 in activated microglia. More importantly, by purifying microglia/macrophage derived exosomes in the CSF of Parkinson's disease patients, we confirmed the presence of α-synuclein oligomer in CD11b+ exosomes, which were able to induce α-synuclein aggregation in neurons, further supporting the translational aspect of this study. Taken together, our study supports the view that microglial exosomes contribute to the progression of α-synuclein pathology and therefore, they may serve as a promising therapeutic target for Parkinson's disease.
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Affiliation(s)
- Min Guo
- Department of Neurology, Huashan hospital, Fudan University, Shanghai, China
| | - Jian Wang
- Department of Neurology, Huashan hospital, Fudan University, Shanghai, China.,Department of Neurology and National Clinical Research Center for Aging and Medicine, Huashan hospital, Fudan University, Shanghai, China
| | - Yanxin Zhao
- Department of Neurology, The 10th People's Hospital, Tongji University, Shanghai, China
| | - Yiwei Feng
- Department of Neurology, Huashan hospital, Fudan University, Shanghai, China
| | - Sida Han
- Department of Neurology, Huashan hospital, Fudan University, Shanghai, China
| | - Qiang Dong
- Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
| | - Mei Cui
- Department of Neurology, Huashan hospital, Fudan University, Shanghai, China
| | - Kim Tieu
- Department of Environmental Health Sciences, Florida International University, Miami, FL, USA
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27
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Autophagy and Redox Homeostasis in Parkinson's: A Crucial Balancing Act. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8865611. [PMID: 33224433 PMCID: PMC7671810 DOI: 10.1155/2020/8865611] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/23/2020] [Accepted: 10/14/2020] [Indexed: 12/13/2022]
Abstract
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated primarily from endogenous biochemical reactions in mitochondria, endoplasmic reticulum (ER), and peroxisomes. Typically, ROS/RNS correlate with oxidative damage and cell death; however, free radicals are also crucial for normal cellular functions, including supporting neuronal homeostasis. ROS/RNS levels influence and are influenced by antioxidant systems, including the catabolic autophagy pathways. Autophagy is an intracellular lysosomal degradation process by which invasive, damaged, or redundant cytoplasmic components, including microorganisms and defunct organelles, are removed to maintain cellular homeostasis. This process is particularly important in neurons that are required to cope with prolonged and sustained operational stress. Consequently, autophagy is a primary line of protection against neurodegenerative diseases. Parkinson's is caused by the loss of midbrain dopaminergic neurons (mDANs), resulting in progressive disruption of the nigrostriatal pathway, leading to motor, behavioural, and cognitive impairments. Mitochondrial dysfunction, with associated increases in oxidative stress, and declining proteostasis control, are key contributors during mDAN demise in Parkinson's. In this review, we analyse the crosstalk between autophagy and redoxtasis, including the molecular mechanisms involved and the detrimental effect of an imbalance in the pathogenesis of Parkinson's.
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Chen M, Yang LL, Hu ZW, Qin C, Zhou LQ, Duan YL, Bosco DB, Wu LJ, Zhan KB, Xu SB, Tian DS. Deficiency of microglial Hv1 channel is associated with activation of autophagic pathway and ROS production in LPC-induced demyelination mouse model. J Neuroinflammation 2020; 17:333. [PMID: 33158440 PMCID: PMC7646080 DOI: 10.1186/s12974-020-02020-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 10/30/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Multiple sclerosis (MS) is an immune-mediated demyelinated disease of the central nervous system. Activation of microglia is involved in the pathogenesis of myelin loss. OBJECTIVE This study is focused on the role of Hv1 in regulating demyelination and microglial activation through reactive oxygen species (ROS) production after lysophosphatidylcholine (LPC)-mediated demyelination. We also explored autophagy in this process. METHODS A model of demyelination using two-point LPC injection into the corpus callosum was established. LFB staining, immunofluorescence, Western blot, and electron microscopy were used to study the severity of demyelination. Microglial phenotype and autophagy were detected by immunofluorescence and Western blot. Morris water maze was used to test spatial learning and memory ability. RESULTS We have identified that LPC-mediated myelin damage was reduced by Hv1 deficiency. Furthermore, we found that ROS and autophagy of microglia increased in the demyelination region, which was also inhibited by Hv1 knockout. CONCLUSION These results suggested that microglial Hv1 deficiency ameliorates demyelination through inhibition of ROS-mediated autophagy and microglial phenotypic transformation.
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Affiliation(s)
- Man Chen
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China
| | - Lin-Lin Yang
- Department of Neurology, Second Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Zi-Wei Hu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China
| | - Chuan Qin
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China
| | - Luo-Qi Zhou
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China
| | - Ya-Ling Duan
- Department of Neurology, Second Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Dale B Bosco
- Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Long-Jun Wu
- Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Ke-Bin Zhan
- Department of Neurology, Second Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, People's Republic of China.
| | - Sha-Bei Xu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China.
| | - Dai-Shi Tian
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China.
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Yang H, Song X, Wei Z, Xia C, Wang J, Shen L, Wang J. TLR4/MyD88/NF-κB Signaling in the Rostral Ventrolateral Medulla Is Involved in the Depressor Effect of Candesartan in Stress-Induced Hypertensive Rats. ACS Chem Neurosci 2020; 11:2978-2988. [PMID: 32898417 DOI: 10.1021/acschemneuro.0c00029] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
This study aimed to investigate whether the proinflammatory and pressor effects of endogenous angiotensin II (AngII) are mediated by binding to the AngII type 1 receptor (AT1R) and subsequently activating central Toll-like receptor 4 (TLR4) in the rostral ventrolateral medulla (RVLM) of stress-induced hypertensive rats (SIHR). The stress-induced hypertension (SIH) model was established by random electric foot shocks combined with noise stimulation. Mean arterial pressure, heart rate, plasma norepinephrine, and RVLM AngII and TLR4 increased in a time-dependent manner in SIHR. Pro-inflammatory cytokines (tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β)), myeloid differentiation factor 88 (MyD88), and nuclear factor (NF)-κB also increased, while anti-inflammatory cytokine IL-10 decreased in the RVLM of SIHR. These changes were attenuated by 14-day intracerebroventricular (ICV) infusion of VIPER (a TLR4 inhibitor) or candesartan (an AT1R antagonist). Both TLR4 and AT1R were expressed in the neurons and microglia in the RVLM of SIHR. Candesartan attenuated the expression of TLR4 in the RVLM of SIHR. This study demonstrated that endogenous AngII may activate AT1R to upregulate TLR4/MyD88/NF-κB signaling and subsequently trigger an inflammatory response in the RVLM of SIHR, which in turn enhanced sympathetic activity and increased blood pressure.
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Affiliation(s)
- Hongyu Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xiaoshan Song
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Zhimiao Wei
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Chunmei Xia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jijiang Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Linlin Shen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jin Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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Cannabinoid type 2 receptor agonist JWH133 decreases blood pressure of spontaneously hypertensive rats through relieving inflammation in the rostral ventrolateral medulla of the brain. J Hypertens 2020; 38:886-895. [DOI: 10.1097/hjh.0000000000002342] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Hu L, Zhang S, Ooi K, Wu X, Wu J, Cai J, Sun Y, Wang J, Zhu D, Chen F, Xia C. Microglia-Derived NLRP3 Activation Mediates the Pressor Effect of Prorenin in the Rostral Ventrolateral Medulla of Stress-Induced Hypertensive Rats. Neurosci Bull 2020; 36:475-492. [PMID: 32242284 PMCID: PMC7186257 DOI: 10.1007/s12264-020-00484-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 12/14/2019] [Indexed: 02/07/2023] Open
Abstract
Increased microglial activation and neuroinflammation within autonomic brain regions such as the rostral ventrolateral medulla (RVLM) have been implicated in stress-induced hypertension (SIH). Prorenin, a member of the brain renin-angiotensin system (RAS), can directly activate microglia. The present study aimed to investigate the effects of prorenin on microglial activation in the RVLM of SIH rats. Rats were subjected to intermittent electric foot-shocks plus noise, this stress was administered for 2 h twice daily for 15 consecutive days, and mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were monitored. The results showed that MAP and RSNA were augmented, and this paralleled increased pro-inflammatory phenotype (M1) switching. Prorenin and its receptor (PRR) expression and the NLR family pyrin domain containing 3 (NLRP3) activation were increased in RVLM of SIH rats. In addition, PLX5622 (a microglial depletion agent), MCC950 (a NLRP3 inhibitor), and/or PRO20 (a (Pro)renin receptor antagonist) had antihypertensive effects in the rats. The NLRP3 expression in the RVLM was decreased in SIH rats treated with PLX5622. Mito-tracker staining showed translocation of NLRP3 from mitochondria to the cytoplasm in prorenin-stimulated microglia. Prorenin increased the ROS-triggering M1 phenotype-switching and NLRP3 activation, while MCC950 decreased the M1 polarization. In conclusion, upregulated prorenin in the RVLM may be involved in the pathogenesis of SIH, mediated by activation of the microglia-derived NLRP3 inflammasome. The link between prorenin and NLRP3 in microglia provides insights for the treatment of stress-related hypertension.
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Affiliation(s)
- Li Hu
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, 200444, China
| | - Shutian Zhang
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, 200032, China
| | - Kokwin Ooi
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, 200032, China
| | - Xuehai Wu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jiaxiang Wu
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, 200444, China
| | - Jian Cai
- Department of Neurology, Renji Hospital, Shanghai Jiaotong University, Shanghai, 200240, China
| | - Yinggang Sun
- Department of Cardiovascular Diseases, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jijiang Wang
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, 200032, China
| | - Danian Zhu
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, 200032, China
| | - Fuxue Chen
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, 200444, China.
| | - Chunmei Xia
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, 200032, China.
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Donertas Ayaz B, Zubcevic J. Gut microbiota and neuroinflammation in pathogenesis of hypertension: A potential role for hydrogen sulfide. Pharmacol Res 2020; 153:104677. [PMID: 32023431 PMCID: PMC7056572 DOI: 10.1016/j.phrs.2020.104677] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 11/27/2019] [Accepted: 01/27/2020] [Indexed: 02/06/2023]
Abstract
Inflammation and gut dysbiosis are hallmarks of hypertension (HTN). Hydrogen sulfide (H2S) is an important freely diffusing molecule that modulates the function of neural, cardiovascular and immune systems, and circulating levels of H2S are reduced in animals and humans with HTN. While most research to date has focused on H₂S produced endogenously by the host, H2S is also produced by the gut bacteria and may affect the host homeostasis. Here, we review an association between neuroinflammation and gut dysbiosis in HTN, with special emphasis on a potential role of H2S in this interplay.
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Affiliation(s)
- Basak Donertas Ayaz
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States; Department of Pharmacology, College of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
| | - Jasenka Zubcevic
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States.
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Pomilio C, Gorojod RM, Riudavets M, Vinuesa A, Presa J, Gregosa A, Bentivegna M, Alaimo A, Alcon SP, Sevlever G, Kotler ML, Beauquis J, Saravia F. Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer's disease patients. GeroScience 2020; 42:613-632. [PMID: 31975051 DOI: 10.1007/s11357-020-00161-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 01/16/2020] [Indexed: 01/17/2023] Open
Abstract
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 ubiquitin+ 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 pro-inflammatory conditions and persistent exposure to aggregated Aβ peptides. In addition, we found LC3-positive 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. Graphical abstract.
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Affiliation(s)
- Carlos Pomilio
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Biología y Medicina Experimental (IBYME), CONICET, Obligado 2490, 1428, Buenos Aires, Argentina
| | - Roxana M Gorojod
- Departmento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IQUIBICEN, CONICET, Buenos Aires, Argentina
| | - Miguel Riudavets
- FLENI, Instituto de Investigaciones Neurológicas Dr Raúl Carrea, Buenos Aires, Argentina
| | - Angeles Vinuesa
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Biología y Medicina Experimental (IBYME), CONICET, Obligado 2490, 1428, Buenos Aires, Argentina
| | - Jessica Presa
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Biología y Medicina Experimental (IBYME), CONICET, Obligado 2490, 1428, Buenos Aires, Argentina
| | - Amal Gregosa
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Biología y Medicina Experimental (IBYME), CONICET, Obligado 2490, 1428, Buenos Aires, Argentina
| | - Melisa Bentivegna
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Biología y Medicina Experimental (IBYME), CONICET, Obligado 2490, 1428, Buenos Aires, Argentina
| | - Agustina Alaimo
- Departmento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IQUIBICEN, CONICET, Buenos Aires, Argentina
| | - Soledad Porte Alcon
- Departmento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IQUIBICEN, CONICET, Buenos Aires, Argentina
| | - Gustavo Sevlever
- FLENI, Instituto de Investigaciones Neurológicas Dr Raúl Carrea, Buenos Aires, Argentina
| | - Monica L Kotler
- Departmento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IQUIBICEN, CONICET, Buenos Aires, Argentina
| | - Juan Beauquis
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Biología y Medicina Experimental (IBYME), CONICET, Obligado 2490, 1428, Buenos Aires, Argentina
| | - Flavia Saravia
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Biología y Medicina Experimental (IBYME), CONICET, Obligado 2490, 1428, Buenos Aires, Argentina.
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Zhang S, Hu L, Jiang J, Li H, Wu Q, Ooi K, Wang J, Feng Y, Zhu D, Xia C. HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia. J Neuroinflammation 2020; 17:15. [PMID: 31924219 PMCID: PMC6953162 DOI: 10.1186/s12974-019-1673-3] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 12/11/2019] [Indexed: 12/15/2022] Open
Abstract
Background Microglial mediated neuroinflammation in the rostral ventrolateral medulla (RVLM) plays roles in the etiology of stress-induced hypertension (SIH). It was reported that autophagy influenced inflammation via immunophenotypic switching of microglia. High-mobility group box 1 (HMGB1) acts as a regulator of autophagy and initiates the production of proinflammatory cytokines (PICs), but the underlying mechanisms remain unclear. Methods The stressed mice were subjected to intermittent electric foot shocks plus noises administered for 2 h twice daily for 15 consecutive days. In mice, blood pressure (BP) and renal sympathetic nerve activity (RSNA) were monitored by noninvasive tail-cuff method and platinum-iridium electrodes placed respectively. Microinjection of siRNA-HMGB1 (siHMGB1) into the RVLM of mice to study the effect of HMGB1 on microglia M1 activation was done. mRFP-GFP-tandem fluorescent LC3 (tf-LC3) vectors were transfected into the RVLM to evaluate the process of autolysosome formation/autophagy flux. The expression of RAB7, lysosomal-associated membrane protein 1 (LAMP1), and lysosomal pH change were used to evaluate lysosomal function in microglia. Mitophagy was identified by transmission electron microscopic observation or by checking LC3 and MitoTracker colocalization under a confocal microscope. Results We showed chronic stress increased cytoplasmic translocations of HMGB1 and upregulation of its receptor RAGE expression in microglia. The mitochondria injury, oxidative stress, and M1 polarization were attenuated in the RVLM of stressed Cre-CX3CR1/RAGEfl/fl mice. The HMGB1/RAGE axis increased at the early stage of stress-induced mitophagy flux while impairing the late stages of mitophagy flux in microglia, as revealed by decreased GFP fluorescence quenching of GFP-RFP-LC3-II puncta and decreased colocalization of lysosomes with mitochondria. The expressions of RAB7 and LAMP1 were decreased in the stressed microglia, while knockout of RAGE reversed these effects and caused an increase in acidity of lysosomes. siHMGB1 in the RVLM resulted in BP lowering and RSNA decreasing in SIH mice. When the autophagy inducer, rapamycin, is used to facilitate the mitophagy flux, this treatment results in attenuated NF-κB activation and reduced PIC release in exogenous disulfide HMGB1 (ds-HMGB1)-stimulated microglia. Conclusions Collectively, we demonstrated that inhibition of the HMGB1/RAGE axis activation led to increased stress-induced mitophagy flux, hence reducing the activity of microglia-mediated neuroinflammation and consequently reduced the sympathetic vasoconstriction drive in the RVLM. Electronic supplementary material The online version of this article (10.1186/s12974-019-1673-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shutian Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.,Clinical Medicine (Eight-year Program), Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Li Hu
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, 200444, People's Republic of China
| | - Jialun Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Hongji Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Qin Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Kokwin Ooi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Jijiang Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Yi Feng
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Danian Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Chunmei Xia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.
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Limanaqi F, Busceti CL, Biagioni F, Fornai F, Puglisi-Allegra S. Autophagy-Based Hypothesis on the Role of Brain Catecholamine Response During Stress. Front Psychiatry 2020; 11:569248. [PMID: 33093837 PMCID: PMC7527533 DOI: 10.3389/fpsyt.2020.569248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 08/31/2020] [Indexed: 12/16/2022] Open
Abstract
Stressful events, similar to abused drugs, significantly affect the homeostatic balance of the catecholamine brain systems while activating compensation mechanisms to restore balance. In detail, norepinephrine (NE)- and dopamine (DA)-containing neurons within the locus coeruleus (LC) and ventral tegmental area (VTA), are readily and similarly activated by psychostimulants and stressful events involving neural processes related to perception, reward, cognitive evaluation, appraisal, and stress-dependent hormonal factors. Brain catecholamine response to stress results in time-dependent regulatory processes involving mesocorticolimbic circuits and networks, where LC-NE neurons respond more readily than VTA-DA neurons. LC-NE projections are dominant in controlling the forebrain DA-targeted areas, such as the nucleus accumbens (NAc) and medial pre-frontal cortex (mPFC). Heavy and persistent coping demand could lead to sustained LC-NE and VTA-DA neuronal activity, that, when persisting chronically, is supposed to alter LC-VTA synaptic connections. Increasing evidence has been provided indicating a role of autophagy in modulating DA neurotransmission and synaptic plasticity. This alters behavior, and emotional/cognitive experience in response to drug abuse and occasionally, to psychological stress. Thus, relevant information to address the role of stress and autophagy can be drawn from psychostimulants research. In the present mini-review we discuss the role of autophagy in brain catecholamine response to stress and its dysregulation. The findings here discussed suggest a crucial role of regulated autophagy in the response and adaptation of LC-NE and VTA-DA systems to stress.
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Affiliation(s)
- Fiona Limanaqi
- Department of Translational Research and New Technologies on Medicine and Surgery, University of Pisa, Pisa, Italy
| | | | | | - Francesco Fornai
- Department of Translational Research and New Technologies on Medicine and Surgery, University of Pisa, Pisa, Italy.,IRCCS Neuromed, Pozzilli, Italy
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Su SH, Wu YF, Lin Q, Wang DP, Hai J. URB597 protects against NLRP3 inflammasome activation by inhibiting autophagy dysfunction in a rat model of chronic cerebral hypoperfusion. J Neuroinflammation 2019; 16:260. [PMID: 31815636 PMCID: PMC6900848 DOI: 10.1186/s12974-019-1668-0] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 11/29/2019] [Indexed: 12/24/2022] Open
Abstract
Background Previous studies reported that URB597 (URB) had therapeutic potential for treating chronic cerebral hypoperfusion (CCH)-induced neuroinflammation and autophagy dysfunction. However, the interaction mechanisms underlying the CCH-induced abnormal excessive autophagy and neuroinflammation remain unknown. In this study, we investigated the roles of impaired autophagy in nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing (NLRP) 3 inflammasome activation in the rat hippocampus and the underlying mechanisms under the condition of induced CCH as well as the effect of URB treatment. Methods The CCH rat model was established by bilateral common carotid artery occlusion (BCCAo), and rats were randomly divided into 11 groups as follows: (1) sham-operated, (2) BCCAo; (3) BCCAo+autophagy inhibitor 3-methyladenine (3-MA), (4) BCCAo+lysosome inhibitor chloroquine (CQ), (5) BCCAo+microglial activation inhibitor minocycline, (6) BCCAo+ROS scavenger N-acetylcysteine (NAC), (7) BCCAo+URB, (8) BCCAo+URB+3-MA, (9) BCCAo+URB+CQ, (10) BCCAo+URB+minocycline, (11) BCCAo+URB+NAC. The cell localizations of LC3, p62, LAMP1, TOM20 and NLRP3 were assessed by immunofluorescence staining. The levels of autophagy-related proteins (LC3, p62, LAMP1, BNIP3 and parkin), NLRP3 inflammasome-related proteins (NLRP3, CASP1 and IL-1β), microglial marker (OX-42) and proinflammatory cytokines (iNOS and COX-2) were evaluated by western blotting, and proinflammatory cytokines (IL-1β and TNF-a) were determined by ELISA. Reactive oxygen species (ROS) were assessed by dihydroethidium staining. The mitochondrial ultrastructural changes were examined by electron microscopy. Results CCH induced microglial overactivation and ROS accumulation, promoting the activation of the NLRP3 inflammasome and the release of IL-1β. Blocked autophagy and mitophagy flux enhanced the activation of the NLRP3-CASP1 inflammasome pathway. However, URB alleviated impaired autophagy and mitophagy by decreasing mitochondrial ROS and microglial overactivation as well as restoring lysosomal function, which would further inhibit the activation of the NLRP3-CASP1 inflammasome pathway. Conclusion These findings extended previous studies indicating the function of URB in the mitigation of chronic ischemic injury of the brain.
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Affiliation(s)
- Shao-Hua Su
- Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, China.
| | - Yi-Fang Wu
- Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, China
| | - Qi Lin
- Department of Pharmacy, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Da-Peng Wang
- Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, China
| | - Jian Hai
- Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, China.
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Wang YF, Chen XD, Wang G, Li QY, Liang XY, Sima YH, Xu SQ. Influence of hyperproteinemia on reproductive development in an invertebrate model. Int J Biol Sci 2019; 15:2170-2181. [PMID: 31592097 PMCID: PMC6775287 DOI: 10.7150/ijbs.33310] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 06/09/2019] [Indexed: 12/25/2022] Open
Abstract
Hyperproteinemia is a severe metabolic disease characterized by abnormally elevated plasma protein concentrations (PPC). However, there is currently no reliable animal model for PPC, and the pathological mechanism of hyperproteinemia thus remains unclear. In this study, we evaluated the effects of hyperproteinemia on reproductive development in an invertebrate silkworm model with a controllable PPC and no primary disease effects. High PPC inhibited the synthesis of vitellogenin and 30K protein essential for female ovarian development in the fat body of metabolic tissues, and inhibited their transport through the hemolymph to the ovary. High PPC also induced programmed cell death in testis and ovary cells, slowed the development of germ cells, and significantly reduced the reproductive coefficient. Furthermore, the intensities and mechanisms of high-PPC-induced reproductive toxicity differed between sexes in this silkworm model.
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Affiliation(s)
- Yong-Feng Wang
- School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou 215123, China.,Institute of Agricultural Biotechnology & Ecology (IABE), Soochow University, Suzhou 215123, China
| | - Xue-Dong Chen
- School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou 215123, China.,Institute of Agricultural Biotechnology & Ecology (IABE), Soochow University, Suzhou 215123, China
| | - Guang Wang
- School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou 215123, China.,Institute of Agricultural Biotechnology & Ecology (IABE), Soochow University, Suzhou 215123, China
| | - Qiu-Ying Li
- School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou 215123, China.,Institute of Agricultural Biotechnology & Ecology (IABE), Soochow University, Suzhou 215123, China
| | - Xin-Yin Liang
- School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou 215123, China.,Institute of Agricultural Biotechnology & Ecology (IABE), Soochow University, Suzhou 215123, China
| | - Yang-Hu Sima
- School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou 215123, China.,Institute of Agricultural Biotechnology & Ecology (IABE), Soochow University, Suzhou 215123, China
| | - Shi-Qing Xu
- School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou 215123, China.,Institute of Agricultural Biotechnology & Ecology (IABE), Soochow University, Suzhou 215123, China
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Ma A, Hong J, Shanks J, Rudebush T, Yu L, Hackfort BT, Wang H, Zucker IH, Gao L. Upregulating Nrf2 in the RVLM ameliorates sympatho-excitation in mice with chronic heart failure. Free Radic Biol Med 2019; 141:84-92. [PMID: 31181253 PMCID: PMC6718296 DOI: 10.1016/j.freeradbiomed.2019.06.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/22/2019] [Accepted: 06/03/2019] [Indexed: 11/22/2022]
Abstract
Nuclear factor E2-related factor 2 (Nrf2) is a key transcription factor that maintains redox homeostasis by governing a broad array of antioxidant genes in response to oxidant stress. We hypothesized that overexpression of Nrf2 in the rostral ventrolateral medulla (RVLM) ameliorates sympatho-excitation in mice with coronary artery ligation-induced chronic heart failure (CHF). To address this, we overexpressed Nrf2 in the RVLM using an HIV-CamKIIa-Nrf2 lenti virus in C57BL/6 mice. In addition, we used a Lenti-Cre virus in Keap1flox/flox mice to upregulate Nrf2 non-selectively in the RVLM. Arterial blood pressure (AP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded under conscious and anesthetized conditions, respectively. Protein expression was assayed using western blotting and immunofluorescence staining. We found that (1) Nrf2 and two target proteins, NQO1 and HO-1 in the RVLM were significantly lower in CHF compared to Sham mice. Nrf2 viral transfection of the RVLM upregulated Nrf2 protein. (2) Urinary NE excretion in CHF mice was markedly attenuated following Nrf2 upregulation (812 ± 133 vs 1120 ± 271 ng/24hr mean. ±SE, *p < 0.05, n = 8/group). (3) In the conscious state, CHF mice overexpressing Nrf2 exhibited an enhancement in spontaneous baroreflex gain and in phenylephrine-induced baroreflex control of HR. (4) Acute experiments under anesthetisa revealed a significant decrease in basal RSNA (44.0 ± 6.5 vs 64.7 ± 8.3% of Max. *P < 0.05 n = 8/group) and enhancement in baroreflex sensitivity (Maximal gain -1.8 ± 0.3 vs 1.1 ± 0.2 of mmHg. **p < 0.01. n = 6/group) in CHF mice that were virally transfected with Nrf2 compared with CHF mice transfected with Lenti-GFP. Finally, Lenti-Cre viral overexpression of Nrf2 in Keap1flox/flox mice reduced Keap1 protein and increased Nrf2, NQO1, and HO-1 in the RVLM of Sham and CHF mice. CHF-Cre mice exhibited a significant decrease in baseline RSNA and plasma NE concentration (8.9 ± 1.1 vs 12.7 ± 0.9 ng/mL *P < 0.05 n = 6/group) as compared with CHF-GFP mice. Based on the above data, we conclude that upregulating Nrf2 selectively in the RVLM attenuates sympatho-excitation in CHF mice. Nrf2 may be an important central target for autonomic modulation in cardiovascular disease and during stress.
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Affiliation(s)
- Anyun Ma
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198-5850, USA
| | - Juan Hong
- Department of Anesthesiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198-5850, USA
| | - Julia Shanks
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198-5850, USA
| | - Tara Rudebush
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198-5850, USA
| | - Li Yu
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198-5850, USA
| | - Bryan T Hackfort
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198-5850, USA
| | - Hanjun Wang
- Department of Anesthesiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198-5850, USA
| | - Irving H Zucker
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198-5850, USA.
| | - Lie Gao
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198-5850, USA.
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Abstract
Ion channels play as a pivotal role in hypertension in the processes of maintenance of vascular tone and sympathetic excitement of hypertension. The Kv10.2 channel (encoded by the Kcnh5 gene) belongs to the EAG voltage-gated superfamily. It is distributed widely in the brain, such as the hippocampus, the cortex, and the olfactory bulb. To date, the expression of Kv10.2 in central nervous system nuclei that regulates cardiovascular function and its inter-relationship with hypertension are still unclear. Here, electric foot-shock stressors with noise were used to establish the stress-induced hypertensive (SIH) rat model. The expression of Kv10.2 in the rostral ventrolateral medulla, the nucleus tractus solitarius, and the paraventricular nucleus (PVN) was examined by immunohistochemical staining and western blots. The following results were obtained: (a) the expression level of Kv10.2 was increased obviously in the paraventricular nucleus of SIH rats, whereas no significant difference was found in the rostral ventrolateral medulla and the nucleus tractus solitarius. (b) Kv10.2 was located in neurons. (c) Vesicular glutamate transporter 1 as a protein mark of glutamate neurons was increased in the paraventricular nucleus of the SIH group. (d) The expression of vesicular glutamate transporter 1 protein in neurons was significantly decreased when the Kcnh5 gene was knocked down by small interfering RNA in vitro. These findings indicate that the changes in Kv10.2 may be related to SIH, which may provide a potential avenue for further investigation of SIH.
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Wu Q, Mi Y, Cheng W, Xia C, Zhu D, Du D. Infiltrating T helper 17 cells in the paraventricular nucleus are pathogenic for stress-induced hypertension. Biochem Biophys Res Commun 2019; 515:169-175. [PMID: 31133377 DOI: 10.1016/j.bbrc.2019.05.121] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 05/19/2019] [Indexed: 01/04/2023]
Abstract
Central neuroinflammation produced by both innate and adaptive immunities plays a major role in the development of stress-induced hypertension (SIH), but successful T cell immunoregulation for SIH requires that the T cells can access brain tissues. So far, both the effects of T helper 17 (Th17) cells on SIH and the pathway for T cells entry into the brain were unknown. Here we show that the blood pressure (BP), heart rate (HR) and the norepinephrine(NE) of the SIH rats were considerably higher, the numbers of Th17 cells and IL-17 were higher, relative to control. Anti-IL-17 attenuated the elevation of BP and HR of the SIH rats when microinjected into the paraventricular nucleus (PVN).Alb-FITC, after infusion into the carotid artery, were found in the brain parenchyma of the PVN in the SIH rats. We concluded that Th17 cells infiltrated the parenchyma of the paraventricular nucleus (PVN) via a compromised blood brain barrier (BBB) in response to stress and Th17 cells and IL-17 play an important role in the pathophysiology of SIH.
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Affiliation(s)
- Qin Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Yang Mi
- School of Life Science, Shanghai University, Shanghai, 200444, China
| | - Wenjing Cheng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Chunmei Xia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China
| | - Danian Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China.
| | - Dongshu Du
- School of Life Science, Shanghai University, Shanghai, 200444, China.
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Cell Clearing Systems Bridging Neuro-Immunity and Synaptic Plasticity. Int J Mol Sci 2019; 20:ijms20092197. [PMID: 31060234 PMCID: PMC6538995 DOI: 10.3390/ijms20092197] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 04/29/2019] [Accepted: 04/30/2019] [Indexed: 02/06/2023] Open
Abstract
In recent years, functional interconnections emerged between synaptic transmission, inflammatory/immune mediators, and central nervous system (CNS) (patho)-physiology. Such interconnections rose up to a level that involves synaptic plasticity, both concerning its molecular mechanisms and the clinical outcomes related to its behavioral abnormalities. Within this context, synaptic plasticity, apart from being modulated by classic CNS molecules, is strongly affected by the immune system, and vice versa. This is not surprising, given the common molecular pathways that operate at the cross-road between the CNS and immune system. When searching for a common pathway bridging neuro-immune and synaptic dysregulations, the two major cell-clearing cell clearing systems, namely the ubiquitin proteasome system (UPS) and autophagy, take center stage. In fact, just like is happening for the turnover of key proteins involved in neurotransmitter release, antigen processing within both peripheral and CNS-resident antigen presenting cells is carried out by UPS and autophagy. Recent evidence unravelling the functional cross-talk between the cell-clearing pathways challenged the traditional concept of autophagy and UPS as independent systems. In fact, autophagy and UPS are simultaneously affected in a variety of CNS disorders where synaptic and inflammatory/immune alterations concur. In this review, we discuss the role of autophagy and UPS in bridging synaptic plasticity with neuro-immunity, while posing a special emphasis on their interactions, which may be key to defining the role of immunity in synaptic plasticity in health and disease.
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Hu L, Zhang S, Wen H, Liu T, Cai J, Du D, Zhu D, Chen F, Xia C. Melatonin decreases M1 polarization via attenuating mitochondrial oxidative damage depending on UCP2 pathway in prorenin-treated microglia. PLoS One 2019; 14:e0212138. [PMID: 30742657 PMCID: PMC6370243 DOI: 10.1371/journal.pone.0212138] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 01/28/2019] [Indexed: 12/24/2022] Open
Abstract
Accumulating evidence suggests that neuroinflammation and oxidative stress in cardiovascular center contribute to the pathological processes underlying hypertension. Microglia activation triggers the inflammation and oxidative stress. Melatonin is a documented potent anti-inflammatory regent and antioxidant, the underlying roles of melatonin in regulating microglia activation via mitochondria remain unclear. In present study, we investigated the protective role of melatonin in decreasing M1 phenotype switching via attenuating mitochondrial oxidative damage in dependence on uncoupling protein 2 (UCP2) pathway in microglia. Prorenin (20 nmol/L; 24 hr) was used to induce inflammation in cultured microglia. Mitochondrial morphology was detected by transmission electron microscope. The reactive oxygen species (ROS) production by using DCFH-DA fluorescence imaging and mitochondrial membrane potential (MMP, ΔΨm) was evaluated by JC-1 staining. The indicator of the redox status as the ratio of the amount of total NADP+ to total NADPH, and the expression of 6 subunits of NADPH oxidase is measured. The pro-inflammatory cytokines releasing was measured by qPCR. UCP2 and activated AMPKα (p-AMPKα) expression were examined by immunoblot. Melatonin (100 μM) markedly alleviated the M1 microglia phenotype shifting and abnormal mitochondria morphology. Melatonin attenuated prorenin-induced ΔΨm increasing and ROS overproduction. Melatonin decreased the redox ratio (NADP+/NADPH) and the p47phox and gp91phox subunits of NADPH oxidase expression in prorenin-treated microglia. These effects were reversed in the presence of UCP2 siRNA. Our results suggested that the protective effect of melatonin against prorenin-induced M1 phenotype switching via attenuating mitochondrial oxidative damage depending on UCP2 upregulation in prorenin-treated microglia.
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Affiliation(s)
- Li Hu
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, P.R. China
| | - Shutian Zhang
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, P.R. China
| | - Haoyu Wen
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, P.R. China
| | - Tianfeng Liu
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, P.R. China
| | - Jian Cai
- Department of neurology, Renji Hospital, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Dongshu Du
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, P.R. China
| | - Danian Zhu
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, P.R. China
| | - Fuxue Chen
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, P.R. China
- * E-mail: (FXC); (CMX)
| | - Chunmei Xia
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, P.R. China
- * E-mail: (FXC); (CMX)
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Nav1.6 in the vasomotor center is a promising key molecule in the pathophysiology of stress-induced hypertension. Hypertens Res 2019; 42:143-144. [DOI: 10.1038/s41440-018-0141-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 10/19/2018] [Accepted: 10/19/2018] [Indexed: 11/08/2022]
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Bojić T. Editorial: Neurocardiovascular Diseases: New Aspects of the Old Issues. Front Neurosci 2019; 12:1032. [PMID: 30686991 PMCID: PMC6336917 DOI: 10.3389/fnins.2018.01032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 12/20/2018] [Indexed: 11/24/2022] Open
Affiliation(s)
- Tijana Bojić
- Laboratory of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinča, University of Belgrade, Belgrade, Serbia
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Autophagy and Apoptosis Interact to Modulate T-2 Toxin-Induced Toxicity in Liver Cells. Toxins (Basel) 2019; 11:toxins11010045. [PMID: 30650580 PMCID: PMC6356273 DOI: 10.3390/toxins11010045] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/09/2019] [Accepted: 01/11/2019] [Indexed: 01/19/2023] Open
Abstract
T-2 toxin is a mycotoxin generated by Fusarium species which has been shown to be highly toxic to human and animals. T-2 toxin induces apoptosis in various tissues/organs. Apoptosis and autophagy are two closely interconnected processes, which are important for maintaining physiological homeostasis as well as pathogenesis. Here, for the first time, we demonstrated that T-2 toxins induce autophagy in human liver cells (L02). We demonstrated that T-2 toxin induce acidic vesicular organelles formation, concomitant with the alterations in p62/SQSTM1 and LC3-phosphatidylethanolamine conjugate (LC3-II) and the enhancement of the autophagic flux. Using mRFP-GFP-LC3 by lentiviral transduction, we showed T-2 toxin-mediated lysosomal fusion and the formation of autophagosomes in L02 cells. The formation of autophagosomes was further confirmed by transmission electron microcopy. While T-2 toxin induced both autophagy and apoptosis, autophagy appears to be a leading event in the response to T-2 toxin treatment, reflecting its protective role in cells against cellular damage. Activating autophagy by rapamycin (RAPA) inhibited apoptosis, while suppressing autophagy by chloroquine greatly enhanced the T-2 toxin-induced apoptosis, suggesting the crosstalk between autophagy and apoptosis. Taken together, these results indicate that autophagy plays a role in protecting cells from T-2 toxin-induced apoptosis suggesting that autophagy may be manipulated for the alleviation of toxic responses induced by T-2 toxin.
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Chindemi C, Cirielli V, Cima L, Danzi O, Raniero D, Tagliaro F, Turrina S, Eccher A, Ghimenton C, Bortolotti F, Brunelli M, De Leo D. Autophagy pathways in drug abusers after forensic autopsy: LC3B, ph-mTOR and p70S6K analysis. MEDICINE, SCIENCE, AND THE LAW 2019; 59:49-56. [PMID: 30852985 DOI: 10.1177/0025802419828910] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
INTRODUCTION Autophagy plays a role in various central nervous system diseases. Little is known about its molecular activation in drug addiction. Our aim was to investigate the signalling pathways of autophagy in brain tissues from drug abusers. METHODS Twenty-five drug abusers with acute lethal intoxication and 10 controls were medico-legally autopsied. Brain-tissue samples from the parietal cortex and cerebellum were obtained. Expression of LC3B, phospho-mTOR (ph-mTOR) and phospho70S6 Kinase (p70S6K) was identified in tissue microarrays, with three tissue spots per case. Blood, urine or vitreous humour were tested in all cases to identify the acute intoxication. Hair analysis was performed in 14 cases to confirm chronic intoxication; the remaining cases had a documented medical history of chronic abuse. RESULTS The autophagy marker LC3B was always positive on both the cortex and the cerebellum, stratified as strongly in 18 (72%) cases and weakly positive in seven (28%) cases. ph-mTOR was negative in all cases. The p70S6K molecule showed positivity in 14 (56%) cases on cortex tissue. The cerebellum was always negative, except for Purkinje cells. Drug abusers had statistically more double positive cases (LC3B-p70S6K) than controls ( p=0.0094). CONCLUSION Autophagy pathways were activated in our series, and 56% of drug abusers showed simultaneous LC3B-p70S6K immunoexpression on tissue from the parietal cortex and cerebellum. This may be of value in autopsy practice as an indicator of brain damage due to drug abuse and could serve as alternative or additional double sensitive diagnostic method to detect drug-related deaths using a tissue-based rationale.
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Affiliation(s)
- Chiara Chindemi
- 1 Department of Diagnostics and Public Health, Legal Medicine and Forensic Pathology Unit, University and Hospital Trust of Verona, Italy
| | - Vito Cirielli
- 1 Department of Diagnostics and Public Health, Legal Medicine and Forensic Pathology Unit, University and Hospital Trust of Verona, Italy
| | - Luca Cima
- 2 Department of Diagnostics and Public Health, Pathology Unit, University and Hospital Trust of Verona, Italy
| | - Olivia Danzi
- 3 Department of Neurological, Biomedical and Movement Sciences, University and Hospital Trust of Verona, Italy
| | - Dario Raniero
- 1 Department of Diagnostics and Public Health, Legal Medicine and Forensic Pathology Unit, University and Hospital Trust of Verona, Italy
| | - Franco Tagliaro
- 1 Department of Diagnostics and Public Health, Legal Medicine and Forensic Pathology Unit, University and Hospital Trust of Verona, Italy
- 4 Institute of Pharmacy and Translational Medicine, Sechenov First Moscow State Medical University, Russia
| | - Stefania Turrina
- 1 Department of Diagnostics and Public Health, Legal Medicine and Forensic Pathology Unit, University and Hospital Trust of Verona, Italy
| | - Albino Eccher
- 2 Department of Diagnostics and Public Health, Pathology Unit, University and Hospital Trust of Verona, Italy
| | - Claudio Ghimenton
- 2 Department of Diagnostics and Public Health, Pathology Unit, University and Hospital Trust of Verona, Italy
| | - Federica Bortolotti
- 1 Department of Diagnostics and Public Health, Legal Medicine and Forensic Pathology Unit, University and Hospital Trust of Verona, Italy
| | - Matteo Brunelli
- 1 Department of Diagnostics and Public Health, Legal Medicine and Forensic Pathology Unit, University and Hospital Trust of Verona, Italy
| | - Domenico De Leo
- 1 Department of Diagnostics and Public Health, Legal Medicine and Forensic Pathology Unit, University and Hospital Trust of Verona, Italy
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Zhang Y, Whaley-Connell AT, Sowers JR, Ren J. Autophagy as an emerging target in cardiorenal metabolic disease: From pathophysiology to management. Pharmacol Ther 2018; 191:1-22. [PMID: 29909238 PMCID: PMC6195437 DOI: 10.1016/j.pharmthera.2018.06.004] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 06/05/2018] [Indexed: 12/16/2022]
Abstract
Although advances in medical technology and health care have improved the early diagnosis and management for cardiorenal metabolic disorders, the prevalence of obesity, insulin resistance, diabetes, hypertension, dyslipidemia, and kidney disease remains high. Findings from numerous population-based studies, clinical trials, and experimental evidence have consolidated a number of theories for the pathogenesis of cardiorenal metabolic anomalies including resistance to the metabolic action of insulin, abnormal glucose and lipid metabolism, oxidative and nitrosative stress, endoplasmic reticulum (ER) stress, apoptosis, mitochondrial damage, and inflammation. Accumulating evidence has recently suggested a pivotal role for proteotoxicity, the unfavorable effects of poor protein quality control, in the pathophysiology of metabolic dysregulation and related cardiovascular complications. The ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathways, two major although distinct cellular clearance machineries, govern protein quality control by degradation and clearance of long-lived or damaged proteins and organelles. Ample evidence has depicted an important role for protein quality control, particularly autophagy, in the maintenance of metabolic homeostasis. To this end, autophagy offers promising targets for novel strategies to prevent and treat cardiorenal metabolic diseases. Targeting autophagy using pharmacological or natural agents exhibits exciting new strategies for the growing problem of cardiorenal metabolic disorders.
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Affiliation(s)
- Yingmei Zhang
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
| | - Adam T Whaley-Connell
- Research Service, Harry S Truman Memorial Veterans' Hospital, University of Missouri-Columbia School of Medicine, Columbia, MO, USA; Diabetes and Cardiovascular Center, Department of Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO, USA
| | - James R Sowers
- Research Service, Harry S Truman Memorial Veterans' Hospital, University of Missouri-Columbia School of Medicine, Columbia, MO, USA; Diabetes and Cardiovascular Center, Department of Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO, USA
| | - Jun Ren
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
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Upregulation of Nav1.6 expression in the rostral ventrolateral medulla of stress-induced hypertensive rats. Hypertens Res 2018; 41:1013-1022. [PMID: 30287879 DOI: 10.1038/s41440-018-0105-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 04/06/2018] [Accepted: 04/09/2018] [Indexed: 02/07/2023]
Abstract
The rostral ventrolateral medulla (RVLM) plays a key role in mediating the development of stress-induced hypertension (SIH) by excitation and/or inhibition of sympathetic preganglionic neurons. The voltage-gated sodium channel Nav1.6 has been found to contribute to neuronal hyperexcitability. To examine the expression of Nav1.6 in the RVLM during SIH, a rat model was established by administering electric foot-shocks and noises. We found that Nav1.6 protein expression in the RVLM of SIH rats was higher than that of control rats, peaking at the tenth day of stress. Furthermore, we observed changes in blood pressure correlating with days of stress, with systolic blood pressure (SBP) found to reach a similarly timed peak at the tenth day of stress. Percentages of cells exhibiting colocalization of Nav1.6 with NeuN, a molecular marker of neurons, indicated a strong correlation between upregulation of Nav1.6 expression in NeuN-positive cells and SBP. The level of RSNA was significantly increased after 10 days of stress induction than control group. Compared with the SIHR, knockdown of Nav1.6 in RVLM of the SIHR decreased the level of SBP, heart rate (HR) and renal sympathetic nerve activity (RSNA). These results suggest that upregulated Nav1.6 expression within neurons in the RVLM of SIH rats may contribute to overactivation of the sympathetic system in response to SIH development.
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Wang Z, Liu S, Pan W, Guo Y, Shen Z. Bafilomycin A1 alleviates depression‑like symptoms in chronic unpredictable mild stress rats. Mol Med Rep 2018; 18:4587-4594. [PMID: 30221667 DOI: 10.3892/mmr.2018.9431] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 07/19/2018] [Indexed: 12/08/2022] Open
Abstract
Major depression is a multifactorial disease. Emerging evidence has suggested that autophagy is involved in the pathological process of depressive disorders. Bafilomycin A1 (Baf A1), is an inhibitor of vacuolar H+‑ATPase that is frequently used at high concentrations to block late‑phase autophagy. However, whether Baf A1 has antidepressant effects remains to be elucidated. The current study aimed to evaluate the antidepressant effects of Baf A1 in rats with chronic unpredictable mild stress (CUMS) and its potential mechanism. The CUMS animal model was established. The sucrose preference test, open‑field test (OFT) and forced swim test (FST) were applied to evaluate the depressive behavior. Synaptic plasticity‑associated proteins synaptophysin and postsynaptic density protein 95 were measured by western blotting and immunofluorescence. Apoptosis‑ and autophagy‑associated proteins in addition to pro‑inflammatory cytokines, including interleukin‑1β and tumor necrosis factor‑α, were detected by western blotting, reverse transcription‑quantitative polymerase chain reaction or ELISA. A 4‑week treatment period with Baf A1 markedly ameliorated CUMS‑induced behavioral abnormalities, including increasing sucrose intake, improving locomotor activity in the OFT, and decreasing immobility time in the FST. In addition, treatment with Baf A1 restored the dysregulation of synaptic plasticity and inhibited neuroinflammation in rats exposed to CUMS. Furthermore, Baf A1 decreased the levels of apoptosis‑ and autophagy‑associated proteins induced by CUMS. The present study demonstrated that Bafilomycin A1 resulted in antidepressant effects in rats, which may be mediated by the reversal of apoptosis, autophagy and neuroinflammation in the hippocampus.
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Affiliation(s)
- Zhijian Wang
- School of Medicine, Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Shengbing Liu
- School of Medicine, Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Weiwei Pan
- School of Medicine, Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Yanjun Guo
- School of Medicine, Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Zhongfei Shen
- School of Medicine, Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
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Mi Y, Wu Q, Yuan W, Chen F, Du D. Role of microglia M1/M2 polarisation in the paraventricular nucleus: New insight into the development of stress-induced hypertension in rats. Auton Neurosci 2018; 213:71-80. [DOI: 10.1016/j.autneu.2018.06.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 06/08/2018] [Accepted: 06/11/2018] [Indexed: 12/20/2022]
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