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Huang A, Yeum D, Sewaybricker LE, Aleksic S, Thomas M, Melhorn SJ, Earley YF, Schur EA. Update on Hypothalamic Inflammation and Gliosis: Expanding Evidence of Relevance Beyond Obesity. Curr Obes Rep 2025; 14:6. [PMID: 39775194 PMCID: PMC11963668 DOI: 10.1007/s13679-024-00595-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/14/2024] [Indexed: 01/11/2025]
Abstract
PURPOSE OF REVIEW To evaluate the role of hypothalamic inflammation and gliosis in human obesity pathogenesis and other disease processes influenced by obesity. RECENT FINDINGS Recent studies using established and novel magnetic resonance imaging (MRI) techniques to assess alterations in hypothalamic microarchitecture in humans support the presence of hypothalamic inflammation and gliosis in adults and children with obesity. Studies also identify prenatal exposure to maternal obesity or diabetes as a risk factor for hypothalamic inflammation and gliosis and increased obesity risk in offspring. Hypothalamic inflammation and gliosis have been further implicated in reproductive dysfunction (specifically polycystic ovarian syndrome and male hypogonadism), cardiovascular disease namely hypertension, and alterations in the gut microbiome, and may also accelerate neurocognitive aging. The most recent translational studies support the link between hypothalamic inflammation and gliosis and obesity pathogenesis in humans and expand our understanding of its influence on broader aspects of human health.
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Affiliation(s)
- Alyssa Huang
- Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Dabin Yeum
- Department of Medicine, University of Washington, Seattle, WA, USA
| | | | - Sandra Aleksic
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Melbin Thomas
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Susan J Melhorn
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Yumei Feng Earley
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA
| | - Ellen A Schur
- Department of Medicine, University of Washington, Seattle, WA, USA.
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Woods C, Wang G, Milner TA, Glass MJ. Tumor necrosis factor alpha induces NOX2-dependent reactive oxygen species production in hypothalamic paraventricular nucleus neurons following angiotensin II infusion. Neurochem Int 2024; 179:105825. [PMID: 39097233 DOI: 10.1016/j.neuint.2024.105825] [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: 12/21/2023] [Revised: 07/09/2024] [Accepted: 07/31/2024] [Indexed: 08/05/2024]
Abstract
There is evidence that tumor necrosis factor alpha (TNFα) influences autonomic processes coordinated within the hypothalamic paraventricular nucleus (PVN), however, the signaling mechanisms subserving TNFα's actions in this brain area are unclear. In non-neuronal cell types, TNFα has been shown to play an important role in canonical NADPH oxidase (NOX2)-mediated production of reactive oxygen species (ROS), molecules also known to be critically involved in hypertension. However, little is known about the role of TNFα in NOX2-dependent ROS production in the PVN within the context of hypertension. Using dual labeling immunoelectron microscopy and dihydroethidium (DHE) microfluorography, we provide structural and functional evidence for interactions between TNFα and NOX2 in the PVN. The TNFα type 1 receptor (TNFR1), the major mediator of TNFα signaling in the PVN, was commonly co-localized with the catalytic gp91phox subunit of NOX2 in postsynaptic sites of PVN neurons. Additionally, there was an increase in dual labeled dendritic profiles following fourteen-day slow-pressor angiotensin II (AngII) infusion. Using DHE microfluorography, it was also shown that TNFα application resulted in a NOX2-dependent increase in ROS in isolated PVN neurons projecting to the spinal cord. Further, TNFα-mediated ROS production was heightened after AngII infusion. The finding that TNFR1 and gp91phox are positioned for rapid interactions, particularly in PVN-spinal cord projection neurons, provides a molecular substrate by which inflammatory signaling and oxidative stress may jointly contribute to AngII hypertension.
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Affiliation(s)
- Clara Woods
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Gang Wang
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Teresa A Milner
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA; Harold and Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Ave, New York, NY, 10065, USA
| | - Michael J Glass
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA.
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Abdulla MH, AlMarabeh S, Bolger T, Lucking EF, O'Halloran KD, Johns EJ. Effects of intrarenal pelvic infusion of tumour necrosis factor-α and interleukin 1-β on reno-renal reflexes in anaesthetised rats. J Hypertens 2024; 42:1027-1038. [PMID: 38690904 DOI: 10.1097/hjh.0000000000003689] [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: 05/03/2024]
Abstract
OBJECTIVE Reno-renal reflexes are disturbed in cardiovascular and hypertensive conditions when elevated levels of pro-inflammatory mediators/cytokines are present within the kidney. We hypothesised that exogenously administered inflammatory cytokines tumour necrosis factor alpha (TNF-α) and interleukin (IL)-1β modulate the renal sympatho-excitatory response to chemical stimulation of renal pelvic sensory nerves. METHODS In anaesthetised rats, intrarenal pelvic infusions of vehicle [0.9% sodium chloride (NaCl)], TNF-α (500 and 1000 ng/kg) and IL-1β (1000 ng/kg) were maintained for 30 min before chemical activation of renal pelvic sensory receptors was performed using randomized intrarenal pelvic infusions of hypertonic NaCl, potassium chloride (KCl), bradykinin, adenosine and capsaicin. RESULTS The increase in renal sympathetic nerve activity (RSNA) in response to intrarenal pelvic hypertonic NaCl was enhanced during intrapelvic TNF-α (1000 ng/kg) and IL-1β infusions by almost 800% above vehicle with minimal changes in mean arterial pressure (MAP) and heart rate (HR). Similarly, the RSNA response to intrarenal pelvic adenosine in the presence of TNF-α (500 ng/kg), but not IL-1β, was almost 200% above vehicle but neither MAP nor HR were changed. There was a blunted sympatho-excitatory response to intrapelvic bradykinin in the presence of TNF-α (1000 ng/kg), but not IL-1β, by almost 80% below vehicle, again without effect on either MAP or HR. CONCLUSION The renal sympatho-excitatory response to renal pelvic chemoreceptor stimulation is modulated by exogenous TNF-α and IL-1β. This suggests that inflammatory mediators within the kidney can play a significant role in modulating the renal afferent nerve-mediated sympatho-excitatory response.
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Affiliation(s)
- Mohammed H Abdulla
- Department of Physiology, School of Medicine, College of Medicine and Health, University College Cork, Cork, Ireland
| | - Sara AlMarabeh
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Amman, Jordan
| | - Tom Bolger
- Department of Physiology, School of Medicine, College of Medicine and Health, University College Cork, Cork, Ireland
| | - Eric F Lucking
- Department of Physiology, School of Medicine, College of Medicine and Health, University College Cork, Cork, Ireland
| | - Ken D O'Halloran
- Department of Physiology, School of Medicine, College of Medicine and Health, University College Cork, Cork, Ireland
| | - Edward J Johns
- Department of Physiology, School of Medicine, College of Medicine and Health, University College Cork, Cork, Ireland
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Zhang H, Dhalla NS. The Role of Pro-Inflammatory Cytokines in the Pathogenesis of Cardiovascular Disease. Int J Mol Sci 2024; 25:1082. [PMID: 38256155 PMCID: PMC10817020 DOI: 10.3390/ijms25021082] [Citation(s) in RCA: 115] [Impact Index Per Article: 115.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
With cardiovascular disease (CVD) being a primary source of global morbidity and mortality, it is crucial that we understand the molecular pathophysiological mechanisms at play. Recently, numerous pro-inflammatory cytokines have been linked to several different CVDs, which are now often considered an adversely pro-inflammatory state. These cytokines most notably include interleukin-6 (IL-6),tumor necrosis factor (TNF)α, and the interleukin-1 (IL-1) family, amongst others. Not only does inflammation have intricate and complex interactions with pathophysiological processes such as oxidative stress and calcium mishandling, but it also plays a role in the balance between tissue repair and destruction. In this regard, pre-clinical and clinical evidence has clearly demonstrated the involvement and dynamic nature of pro-inflammatory cytokines in many heart conditions; however, the clinical utility of the findings so far remains unclear. Whether these cytokines can serve as markers or risk predictors of disease states or act as potential therapeutic targets, further extensive research is needed to fully understand the complex network of interactions that these molecules encompass in the context of heart disease. This review will highlight the significant advances in our understanding of the contributions of pro-inflammatory cytokines in CVDs, including ischemic heart disease (atherosclerosis, thrombosis, acute myocardial infarction, and ischemia-reperfusion injury), cardiac remodeling (hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac apoptosis, and heart failure), different cardiomyopathies as well as ventricular arrhythmias and atrial fibrillation. In addition, this article is focused on discussing the shortcomings in both pathological and therapeutic aspects of pro-inflammatory cytokines in CVD that still need to be addressed by future studies.
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Affiliation(s)
- Hannah Zhang
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Naranjan S. Dhalla
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
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Dellacqua LO, Gomes PM, Batista JS, Michelini LC, Antunes VR. Exercise-induced neuroplasticity in autonomic nuclei restores the cardiac vagal tone and baroreflex dysfunction in aged hypertensive rats. J Appl Physiol (1985) 2024; 136:189-198. [PMID: 38059293 DOI: 10.1152/japplphysiol.00433.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 11/29/2023] [Accepted: 12/01/2023] [Indexed: 12/08/2023] Open
Abstract
Aging is accompanied by considerable deterioration of homeostatic systems, such as autonomic imbalance characterized by heightened sympathetic activity, lower parasympathetic tone, and depressed heart rate (HR) variability, which are aggravated by hypertension. Here, we hypothesized that these age-related deficits in aged hypertensive rats can be ameliorated by exercise training, with benefits to the cardiovascular system. Therefore, male 22-mo-old spontaneously hypertensive rats (SHRs) and age-matched Wistar Kyoto (WKY) submitted to moderate-intensity exercise training (T) or kept sedentary (S) for 8 wk were evaluated for hemodynamic/autonomic parameters, baroreflex sensitivity, cardiac sympathetic/parasympathetic tone and analysis of dopamine β-hydroxylase (DBH+) and oxytocin (OT+) pathways of autonomic brain nuclei. Aged SHR-S versus WKY-S exhibited elevated mean arterial pressure (MAP: +51%) and HR (+20%), augmented pressure/HR variability, no cardiac vagal tone, and depressed reflex control of the heart (HR range, -28%; gain, -49%). SHR-T exhibited a lower resting HR, a partial reduction in the MAP (-14%), in the pressure/HR variabilities, and restored parasympathetic modulation, with improvement of baroreceptor reflex control when compared with SHR-S. Exercise training increased the ascending DBH+ projections conveying peripheral information to the paraventricular nucleus of hypothalamus (PVN), augmented the expression of OT+ neurons, and reduced the density of DBH+ neurons in the rostral ventrolateral medulla (RVLM) of SHR-T. Data indicate that exercise training induces beneficial neuroplasticity in brain autonomic circuitry, and it is highly effective to restore the parasympathetic tone, and attenuation of age-related autonomic imbalance and baroreflex dysfunction, thus conferring long-term benefits for cardiovascular control in aged hypertensive individuals.NEW & NOTEWORTHY Exercise training reduces high blood pressure and cardiovascular autonomic modulation in aged hypertensive rats. The dysfunction in the baroreflex sensitivity and impaired parasympathetic tone to the heart of aged hypertensive rats are restored by exercise training. Exercise induces beneficial neuroplasticity in the brain nuclei involved with autonomic control of cardiovascular function of aged hypertensive rats.
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Affiliation(s)
- Lais Oliveira Dellacqua
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Paula Magalhães Gomes
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Julia Santos Batista
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Lisete Compagno Michelini
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Vagner Roberto Antunes
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
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Lauar MR, Colombari DSA, De Paula PM, Colombari E, Andrade CAF, De Luca LA, Menani JV. Chronic administration of catalase inhibitor attenuates hypertension in renovascular hypertensive rats. Life Sci 2023; 319:121538. [PMID: 36868399 DOI: 10.1016/j.lfs.2023.121538] [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: 12/20/2022] [Revised: 02/18/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023]
Abstract
AIMS Reactive oxygen species like hydrogen peroxide (H2O2) are produced endogenously and may participate in intra- and extracellular signaling, including modulation of angiotensin II responses. In the present study, we investigated the effects of chronic subcutaneous (sc) administration of the catalase inhibitor 3-amino-1,2,4-triazole (ATZ) on arterial pressure, autonomic modulation of arterial pressure, hypothalamic expression of AT1 receptors and neuroinflammatory markers and fluid balance in 2-kidney, 1clip (2K1C) renovascular hypertensive rats. MATERIALS AND METHODS Male Holtzman rats with a clip occluding partially the left renal artery and chronic sc injections of ATZ were used. KEY FINDINGS Subcutaneous injections of ATZ (600 mg/kg of body weight/day) for 9 days in 2K1C rats reduced arterial pressure (137 ± 8, vs. saline: 182 ± 8 mmHg). ATZ also reduced the sympathetic modulation and enhanced the parasympathetic modulation of pulse interval, reducing the sympatho-vagal balance. Additionally, ATZ reduced mRNA expression for interleukins 6 and IL-1β, tumor necrosis factor-α, AT1 receptor (0.77 ± 0.06, vs. saline: 1.47 ± 0.26 fold change), NOX 2 (0.85 ± 0.13, vs. saline: 1.75 ± 0.15 fold change) and the marker of microglial activation, CD 11 (0.47 ± 0.07, vs. saline, 1.34 ± 0.15 fold change) in the hypothalamus of 2K1C rats. Daily water and food intake and renal excretion were only slightly modified by ATZ. SIGNIFICANCE The results suggest that the increase of endogenous H2O2 availability with chronic treatment with ATZ had an anti-hypertensive effect in 2K1C hypertensive rats. This effect depends on decreased activity of sympathetic pressor mechanisms and mRNA expression of AT1 receptors and neuroinflammatory markers possibly due to reduced angiotensin II action.
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Affiliation(s)
- Mariana R Lauar
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Débora S A Colombari
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Patrícia M De Paula
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Eduardo Colombari
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Carina A F Andrade
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - Laurival A De Luca
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil
| | - José V Menani
- Department of Physiology and Pathology, School of Dentistry, São Paulo State University, UNESP, Araraquara, SP, Brazil.
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Helman TJ, Headrick JP, Stapelberg NJC, Braidy N. The sex-dependent response to psychosocial stress and ischaemic heart disease. Front Cardiovasc Med 2023; 10:1072042. [PMID: 37153459 PMCID: PMC10160413 DOI: 10.3389/fcvm.2023.1072042] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 04/03/2023] [Indexed: 05/09/2023] Open
Abstract
Stress is an important risk factor for modern chronic diseases, with distinct influences in males and females. The sex specificity of the mammalian stress response contributes to the sex-dependent development and impacts of coronary artery disease (CAD). Compared to men, women appear to have greater susceptibility to chronic forms of psychosocial stress, extending beyond an increased incidence of mood disorders to include a 2- to 4-fold higher risk of stress-dependent myocardial infarction in women, and up to 10-fold higher risk of Takotsubo syndrome-a stress-dependent coronary-myocardial disorder most prevalent in post-menopausal women. Sex differences arise at all levels of the stress response: from initial perception of stress to behavioural, cognitive, and affective responses and longer-term disease outcomes. These fundamental differences involve interactions between chromosomal and gonadal determinants, (mal)adaptive epigenetic modulation across the lifespan (particularly in early life), and the extrinsic influences of socio-cultural, economic, and environmental factors. Pre-clinical investigations of biological mechanisms support distinct early life programming and a heightened corticolimbic-noradrenaline-neuroinflammatory reactivity in females vs. males, among implicated determinants of the chronic stress response. Unravelling the intrinsic molecular, cellular and systems biological basis of these differences, and their interactions with external lifestyle/socio-cultural determinants, can guide preventative and therapeutic strategies to better target coronary heart disease in a tailored sex-specific manner.
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Affiliation(s)
- Tessa J. Helman
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, NSW, Sydney, Australia
- Correspondence: Tessa J. Helman
| | - John P. Headrick
- Schoolof Pharmacy and Medical Sciences, Griffith University, Southport, QLD, Australia
| | | | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, NSW, Sydney, Australia
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Woods C, Contoreggi NH, Johnson MA, Milner TA, Wang G, Glass MJ. Estrogen receptor beta activity contributes to both tumor necrosis factor alpha expression in the hypothalamic paraventricular nucleus and the resistance to hypertension following angiotensin II in female mice. Neurochem Int 2022; 161:105420. [PMID: 36170907 PMCID: PMC11575694 DOI: 10.1016/j.neuint.2022.105420] [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: 07/27/2022] [Revised: 09/13/2022] [Accepted: 09/20/2022] [Indexed: 12/26/2022]
Abstract
Sex differences in the sensitivity to hypertension and inflammatory processes are well characterized but insufficiently understood. In male mice, tumor necrosis factor alpha (TNFα) in the hypothalamic paraventricular nucleus (PVN) contributes to hypertension following slow-pressor angiotensin II (AngII) infusion. However, the role of PVN TNFα in the response to AngII in female mice is unknown. Using a combination of in situ hybridization, high-resolution electron microscopic immunohistochemistry, spatial-temporal gene silencing, and dihydroethidium microfluorography we investigated the influence of AngII on both blood pressure and PVN TNFα signaling in female mice. We found that chronic (14-day) infusion of AngII in female mice did not impact blood pressure, TNFα levels, the expression of the TNFα type 1 receptor (TNFR1), or the subcellular distribution of TNFR1 in the PVN. However, it was shown that blockade of estrogen receptor β (ERβ), a major hypothalamic estrogen receptor, was accompanied by both elevated PVN TNFα and hypertension following AngII. Further, AngII hypertension following ERβ blockade was attenuated by inhibiting PVN TNFα signaling by local TNFR1 silencing. It was also shown that ERβ blockade in isolated PVN-spinal cord projection neurons (i.e. sympathoexcitatory) heightened TNFα-induced production of NADPH oxidase (NOX2)-mediated reactive oxygen species, molecules that may play a key role in mediating the effect of TNFα in hypertension. These results indicate that ERβ contributes to the reduced sensitivity of female mice to hypothalamic inflammatory cytokine signaling and hypertension in response to AngII.
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Affiliation(s)
- Clara Woods
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Natalina H Contoreggi
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Megan A Johnson
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Teresa A Milner
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA; Harold and Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, 10065, USA
| | - Gang Wang
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Michael J Glass
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA.
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Ong WY, Satish RL, Herr DR. ACE2, Circumventricular Organs and the Hypothalamus, and COVID-19. Neuromolecular Med 2022; 24:363-373. [PMID: 35451691 PMCID: PMC9023728 DOI: 10.1007/s12017-022-08706-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/01/2022] [Indexed: 12/29/2022]
Abstract
The SARS-CoV-2 virus gains entry to cells by binding to angiotensin-converting enzyme 2 (ACE2). Since circumventricular organs and parts of the hypothalamus lack a blood-brain barrier, and immunohistochemical studies demonstrate that ACE2 is highly expressed in circumventricular organs which are intimately connected to the hypothalamus, and the hypothalamus itself, these might be easy entry points for SARS-CoV-2 into the brain via the circulation. High ACE2 protein expression is found in the subfornical organ, area postrema, and the paraventricular nucleus of the hypothalamus (PVH). The subfornical organ and PVH are parts of a circuit to regulate osmolarity in the blood, through the secretion of anti-diuretic hormone into the posterior pituitary. The PVH is also the stress response centre in the brain. It controls not only pre-ganglionic sympathetic neurons, but is also a source of corticotropin-releasing hormone, that induces the secretion of adrenocorticotropic hormone from the anterior pituitary. It is proposed that the function of ACE2 in the circumventricular organs and the PVH could be diminished by binding with SARS-CoV-2, thus leading to a reduction in the ACE2/Ang (1-7)/Mas receptor (MasR) signalling axis, that modulates ACE/Ang II/AT1R signalling. This could result in increased presympathetic activity/neuroendocrine secretion from the PVH, and effects on the hypothalamic-pituitary-adrenal axis activity. Besides the bloodstream, the hypothalamus might also be affected by SARS-CoV-2 via transneuronal spread along the olfactory/limbic pathways. Exploring potential therapeutic pathways to prevent or attenuate neurological symptoms of COVID-19, including drugs which modulate ACE signalling, remains an important area of unmet medical need.
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Affiliation(s)
- Wei-Yi Ong
- Department of Anatomy, National University of Singapore, Singapore, 119260, Singapore.
- Neurobiology Research Programme, Life Sciences Institute, National University of Singapore, Singapore, 119260, Singapore.
| | - R L Satish
- Department of Anatomy, National University of Singapore, Singapore, 119260, Singapore
| | - Deron R Herr
- Department of Pharmacology, National University of Singapore, Singapore, 119260, Singapore
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Sabharwal R, Chapleau MW, Gerhold TD, Baumbach GL, Faraci FM. Plasticity of cerebral microvascular structure and mechanics during hypertension and following recovery of arterial pressure. Am J Physiol Heart Circ Physiol 2022; 323:H1108-H1117. [PMID: 36269650 PMCID: PMC9678426 DOI: 10.1152/ajpheart.00292.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 09/28/2022] [Accepted: 10/13/2022] [Indexed: 12/14/2022]
Abstract
Changes in vascular structure contribute to vascular events and loss of brain health. We examined changes in cerebral arterioles at the onset of hypertension and the hypothesis that alterations during hypertension would recover with the return of mean arterial pressure (MAP) to normal. MAP was measured with radiotelemetry in awake male C57BL/6J mice at baseline and during infusion of vehicle or angiotensin II (ANG II, 1.4 mg/kg/day using osmotic pumps) for 28 days, followed by a 28-day recovery. With ANG II treatment, MAP increased through day 28. On day 30, MAP began to recover, reaching levels not different from vehicle on day 37. We measured intravascular pressure, diameter, wall thickness (WT), wall:lumen ratio (W:L), cross-sectional area (CSA), and slope of the tangential elastic modulus (ET) in maximally dilated arterioles. Variables were similar in both groups at day 1, with no significant change with vehicle treatment. With ANG II treatment, CSA, WT, and W:L increased on days 7-28. Internal and external diameter was reduced at 14 and 28 days. ET versus wall stress was reduced on days 7-28. During recovery, the diameter remained at days 14 and 28 values, whereas other variables returned partly or completely to normal. Thus, CSA, WT, W:L, and ET versus wall stress changed rapidly during hypertension and recovered with MAP. In contrast, inward remodeling developed slowly and did not recover. This lack of recovery has mechanistic implications for the long-term impact of hypertension on vascular determinants of brain health.NEW & NOTEWORTHY Changes in vascular structure contribute to vascular events and loss of brain health. We examined the inherent structural plasticity of cerebral arterioles during and after a period of hypertension. Arteriolar wall thickness, diameter, wall-to-lumen ratio, and biological stiffness changed rapidly during hypertension and recovered with blood pressure. In contrast, inward remodeling developed slowly and did not recover. This lack of recovery of arteriolar diameter has implications for the long-term impact of hypertension on vascular determinants of brain health.
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Affiliation(s)
- Rasna Sabharwal
- Department of Internal Medicine, Carver College of Medicine, Francois M. Abboud Cardiovascular Center, University of Iowa, Iowa City, Iowa
- Department of Neuroscience and Pharmacology, Carver College of Medicine, Francois M. Abboud Cardiovascular Center, University of Iowa, Iowa City, Iowa
| | - Mark W Chapleau
- Department of Internal Medicine, Carver College of Medicine, Francois M. Abboud Cardiovascular Center, University of Iowa, Iowa City, Iowa
- Department of Molecular Physiology and Biophysics, Carver College of Medicine, Francois M. Abboud Cardiovascular Center, University of Iowa, Iowa City, Iowa
| | - Thomas D Gerhold
- Department of Internal Medicine, Carver College of Medicine, Francois M. Abboud Cardiovascular Center, University of Iowa, Iowa City, Iowa
| | - Gary L Baumbach
- Department of Pathology, Carver College of Medicine, Francois M. Abboud Cardiovascular Center, University of Iowa, Iowa City, Iowa
| | - Frank M Faraci
- Department of Internal Medicine, Carver College of Medicine, Francois M. Abboud Cardiovascular Center, University of Iowa, Iowa City, Iowa
- Department of Neuroscience and Pharmacology, Carver College of Medicine, Francois M. Abboud Cardiovascular Center, University of Iowa, Iowa City, Iowa
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Gao H, Bigalke J, Jiang E, Fan Y, Chen B, Chen QH, Shan Z. TNFα Triggers an Augmented Inflammatory Response in Brain Neurons from Dahl Salt-Sensitive Rats Compared with Normal Sprague Dawley Rats. Cell Mol Neurobiol 2022; 42:1787-1800. [PMID: 33625627 PMCID: PMC8382783 DOI: 10.1007/s10571-021-01056-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 02/04/2021] [Indexed: 12/23/2022]
Abstract
Tumor Necrosis Factor (TNF)-α is a proinflammatory cytokine (PIC) and has been implicated in a variety of illness including cardiovascular disease. The current study investigated the inflammatory response trigged by TNFα in both cultured brain neurons and the hypothalamic paraventricular nucleus (PVN), a key cardiovascular relevant brain area, of the Sprague Dawley (SD) rats. Our results demonstrated that TNFα treatment induces a dose- and time-dependent increase in mRNA expression of PICs including Interleukin (IL)-1β and Interleukin-6 (IL6); chemokines including C-C Motif Chemokine Ligand 5 (CCL5) and C-C Motif Chemokine Ligand 12 (CCL12), inducible nitric oxide synthase (iNOS), as well as transcription factor NF-kB in cultured brain neurons from neonatal SD rats. Consistent with this finding, immunostaining shows that TNFα treatment increases immunoreactivity of IL1β, CCL5, iNOS and stimulates activation or expression of NF-kB, in both cultured brain neurons and the PVN of adult SD rats. We further compared mRNA expression of the aforementioned genes in basal level as well as in response to TNFα challenge between SD rats and Dahl Salt-sensitive (Dahl-S) rats, an animal model of salt-sensitive hypertension. Dahl-S brain neurons presented higher baseline levels as well as greater response to TNFα challenge in mRNA expression of CCL5, iNOS and IL1β. Furthermore, central administration of TNFα caused significant higher response in CCL12 in the PVN of Dahl-S rats. The increased inflammatory response to TNFα in Dahl-S rats may be indicative of an underlying mechanism for enhanced pressor reactivity to salt intake in the Dahl-S rat model.
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Affiliation(s)
- Huanjia Gao
- Department of Kinesiology & Integrative Physiology, Michigan Technological University, Houghton, MI, 49931, USA
- The Second Clinical College of Guangzhou, University of Chinese Medicine, Guangzhou, China
| | - Jeremy Bigalke
- Department of Kinesiology & Integrative Physiology, Michigan Technological University, Houghton, MI, 49931, USA
| | - Enshe Jiang
- Department of Kinesiology & Integrative Physiology, Michigan Technological University, Houghton, MI, 49931, USA
- Institute of Nursing and Health, Henan University, Henan, China
- Henan International Joint Laboratory of Nuclear Protein Regulation, Henan University, Henan, China
| | - Yuanyuan Fan
- Department of Kinesiology & Integrative Physiology, Michigan Technological University, Houghton, MI, 49931, USA
- School of Life Sciences, Henan University, Henan, China
| | - Bojun Chen
- Department of Emergency, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qing-Hui Chen
- Department of Kinesiology & Integrative Physiology, Michigan Technological University, Houghton, MI, 49931, USA
- Health Research Institute, Michigan Technological University, Houghton, MI, 49931, USA
| | - Zhiying Shan
- Department of Kinesiology & Integrative Physiology, Michigan Technological University, Houghton, MI, 49931, USA.
- Health Research Institute, Michigan Technological University, Houghton, MI, 49931, USA.
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12
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Gupta S, Tiwari V, Tiwari P, Parul, Mishra A, Hanif K, Shukla S. Angiotensin-Converting Enzyme 2 Activation Mitigates Behavioral Deficits and Neuroinflammatory Burden in 6-OHDA Induced Experimental Models of Parkinson's Disease. ACS Chem Neurosci 2022; 13:1491-1504. [PMID: 35533351 DOI: 10.1021/acschemneuro.1c00797] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Hypertension is reported to cause major brain disorders including Parkinson's disease (PD), apart from cardiovascular and chronic kidney disorders. Considering this, for the first time, we explored the effect of modulation of the ACE2/Ang (1-7)/MasR axis using diminazene aceturate (DIZE), an ACE2 activator, in 6-hydroxydopamine (6-OHDA) induced PD model. We found that DIZE treatment improved neuromuscular coordination and locomotor deficits in the 6-OHDA induced PD rat model. Further, the DIZE-mediated activation of ACE2 led to increased tyrosine hydroxylase (TH) and dopamine transporters (DAT) expression in the rat brain, indicating the protection of dopaminergic (DAergic) neurons from 6-OHDA induced neurotoxicity. Moreover, 6-OHDA induced activation of glial cells (astrocytes and microglia) and release of neuroinflammatory mediators were attenuated by DIZE treatment in both in vitro as well as in vivo models of PD. DIZE exerted its effect by activating ACE2 that produced Ang (1-7), a neuroprotective peptide. Ang (1-7) conferred its neuroprotective effect upon binding with the G-protein-coupled MAS receptor that led to the upregulation of cell survival proteins while downregulating apoptotic proteins. Importantly, these findings were further validated by using A-779, a MasR antagonist. The result showed that treatment with A-779 reversed the antioxidative and anti-inflammatory effects of DIZE by decreasing glial activation and neuroinflammatory markers. Although the role of ACE2 in PD pathology needs to be additionally confirmed using transgenic models in either ACE2 overexpressing or knockout mice, still, our study demonstrates that enhancing ACE2 activity could be a novel approach for ameliorating PD pathology.
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Affiliation(s)
- Shivangi Gupta
- Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India
| | - Virendra Tiwari
- Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India
| | - Priya Tiwari
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India
| | - Parul
- Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India
| | - Akanksha Mishra
- Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India
| | - Kashif Hanif
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India
| | - Shubha Shukla
- Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India
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13
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Tumor Necrosis Factor-α-Induced Protein 8-Like 2 Ameliorates Cardiac Hypertrophy by Targeting TLR4 in Macrophages. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9469143. [PMID: 35528518 PMCID: PMC9072033 DOI: 10.1155/2022/9469143] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/04/2022] [Indexed: 11/28/2022]
Abstract
Background Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a novel immunoregulatory protein, has been reported to regulate inflammation and apoptosis. The role of TIPE2 in cardiovascular disease, especially cardiac hypertrophy, has not been elucidated. Thus, the aim of the present study was to explore the role of TIPE2 in cardiac hypertrophy. Methods Mice were subjected to aortic banding (AB) to induce an adverse hypertrophic model. To overexpress TIPE2, mice were injected with a lentiviral vector expressing TIPE2. Echocardiographic and hemodynamic analyses were used to evaluate cardiac function. Neonatal rat cardiomyocytes (NRCMs) and mouse peritoneal macrophages (MPMs) were isolated and stimulated with angiotensin II. NRCMs and MPM were also cocultured and stimulated with angiotensin II. Cells were transfected with Lenti-TIPE2 to overexpress TIPE2. Results TIPE2 expression levels were downregulated in hypertrophic mouse hearts and in macrophages in heart tissue. TIPE2 overexpression attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, we found that TIPE2 overexpression in neonatal cardiomyocytes did not relieve the angiotensin II-induced hypertrophic response in vitro. Furthermore, TIPE2 overexpression downregulated TLR4 and NF-κB signaling in macrophages but not in cardiomyocytes, which led to diminished inflammation in macrophages and consequently reduced the activation of hypertrophic Akt signaling in cardiomyocytes. TLR4 inhibition by TAK-242 did not enhance the antihypertrophic effect of TIPE2 overexpression. Conclusions The present study indicated that TIPE2 represses macrophage activation by targeting TLR4, subsequently inhibiting cardiac hypertrophy.
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Wang G, Woods C, Johnson MA, Milner TA, Glass MJ. Angiotensin II Infusion Results in Both Hypertension and Increased AMPA GluA1 Signaling in Hypothalamic Paraventricular Nucleus of Male but not Female Mice. Neuroscience 2022; 485:129-144. [PMID: 34999197 PMCID: PMC9116447 DOI: 10.1016/j.neuroscience.2021.12.041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 10/19/2022]
Abstract
The hypothalamic paraventricular nucleus (PVN) plays a key role in hypertension, however the signaling pathways that contribute to the adaptability of the PVN during hypertension are uncertain. We present evidence that signaling at the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor contributes to increased blood pressure in a model of neurogenic hypertension induced by 14-day slow-pressor angiotensin II (AngII) infusion in male mice. It was found that AngII hypertension was associated with an increase in plasma membrane affiliation of GluA1, but decreased GluA2, in dendritic profiles of PVN neurons expressing the TNFα type 1 receptor, a modulator of AMPA receptor trafficking. The increased plasma membrane GluA1 was paralleled by heightened AMPA currents in PVN-spinal cord projection neurons from AngII-infused male mice. Significantly, elevated AMPA currents in AngII-treated mice were blocked by 1-Naphthyl acetyl spermine trihydrochloride, pointing to the involvement of GluA2-lacking GluA1 receptors in the heightened AMPA signaling in PVN neurons. A further functional role for GluA1 in the PVN was demonstrated by the attenuated hypertensive response following silencing of GluA1 in the PVN of AngII-infused male mice. In female mice, AngII-infusion did not impact blood pressure or plasma membrane localization of GluA1 . Post-translational modifications that increase the plasma membrane localization of AMPA GluA1 and heighten the rapid excitatory signaling actions of glutamate in PVN neurons may serve as a molecular substrate underlying sex differences in hypertension.
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Affiliation(s)
- Gang Wang
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
| | - Clara Woods
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
| | - Megan A. Johnson
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065
| | - Teresa A. Milner
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065,Harold and Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065
| | - Michael J. Glass
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065,Address correspondence to: Dr. Michael J. Glass, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY 10065; Phone: (646) 962-8253;
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15
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Yu XJ, Xiao T, Liu XJ, Li Y, Qi J, Zhang N, Fu LY, Liu KL, Li Y, Kang YM. Effects of Nrf1 in Hypothalamic Paraventricular Nucleus on Regulating the Blood Pressure During Hypertension. Front Neurosci 2021; 15:805070. [PMID: 34938159 PMCID: PMC8685333 DOI: 10.3389/fnins.2021.805070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 11/15/2021] [Indexed: 12/03/2022] Open
Abstract
The incidence rate and mortality of hypertension increase every year. Hypothalamic paraventricular nucleus (PVN) plays a critical role on the pathophysiology of hypertension. It has been demonstrated that the imbalance of neurotransmitters including norepinephrine (NE), glutamate (Glu) and γ-aminobutyric acid (GABA) are closely related to sympathetic overactivity and pathogenesis of hypertension. N-methyl-D-aspartate receptor (NMDAR), consisting of GluN1 and GluN2 subunits, is considered to be a glutamate-gated ion channel, which binds to Glu, and activates neuronal activity. Studies have found that the synthesis of respiratory chain enzyme complex was affected and mitochondrial function was impaired in spontaneously hypertensive rats (SHR), further indicating that mitochondria is associated with hypertension. Nuclear respiratory factor 1 (Nrf1) is a transcription factor that modulates mitochondrial respiratory chain and is related to GluN1, GluN2A, and GluN2B promoters. However, the brain mechanisms underlying PVN Nrf1 modulating sympathoexcitation and blood pressure during the development of hypertension remains unclear. In this study, an adeno-associated virus (AAV) vector carrying the shRNA targeting rat Nrf1 gene (shNrf1) was injected into bilateral PVN of male rats underwent two kidneys and one clip to explore the role of Nrf1 in mediating the development of hypertension and sympathoexcitation. Administration of shNrf1 knocked down the expression of Nrf1 and reduced the expression of excitatory neurotransmitters, increased the expression of inhibitory neurotransmitters, and reduced the production of reactive oxygen species (ROS), and attenuated sympathoexcitation and hypertension. The results indicate that knocking down Nrf1 suppresses sympathoexcitation in hypertension by reducing PVN transcription of NMDAR subunits (GluN1, GluN2A, and GluN2B), rebalancing PVN excitatory and inhibitory neurotransmitters, inhibiting PVN neuronal activity and oxidative stress, and attenuating sympathetic activity.
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Affiliation(s)
- Xiao-Jing Yu
- Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Department of Physiology and Pathophysiology, Shaanxi Engineering and Research Center of Vaccine, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an, China
| | - Tong Xiao
- Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Department of Physiology and Pathophysiology, Shaanxi Engineering and Research Center of Vaccine, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an, China
| | - Xiao-Jing Liu
- Department of Cardiology, The Second Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Ying Li
- Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Department of Physiology and Pathophysiology, Shaanxi Engineering and Research Center of Vaccine, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an, China
| | - Jie Qi
- Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Department of Physiology and Pathophysiology, Shaanxi Engineering and Research Center of Vaccine, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an, China
| | - Nianping Zhang
- Department of Clinical Medicine, Shanxi Datong University School of Medicine, Datong, China
| | - Li-Yan Fu
- Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Department of Physiology and Pathophysiology, Shaanxi Engineering and Research Center of Vaccine, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an, China
| | - Kai-Li Liu
- Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Department of Physiology and Pathophysiology, Shaanxi Engineering and Research Center of Vaccine, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an, China
| | - Yanjun Li
- Department of Microbiology and Immunology, Shanxi Datong University School of Medicine, Datong, China
| | - Yu-Ming Kang
- Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Department of Physiology and Pathophysiology, Shaanxi Engineering and Research Center of Vaccine, Xi'an Jiaotong University School of Basic Medical Sciences, Xi'an, China
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16
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Youwakim J, Girouard H. Inflammation: A Mediator Between Hypertension and Neurodegenerative Diseases. Am J Hypertens 2021; 34:1014-1030. [PMID: 34136907 DOI: 10.1093/ajh/hpab094] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 05/03/2021] [Accepted: 06/15/2021] [Indexed: 12/14/2022] Open
Abstract
Hypertension is the most prevalent and modifiable risk factor for stroke, vascular cognitive impairment, and Alzheimer's disease. However, the mechanistic link between hypertension and neurodegenerative diseases remains to be understood. Recent evidence indicates that inflammation is a common pathophysiological trait for both hypertension and neurodegenerative diseases. Low-grade chronic inflammation at the systemic and central nervous system levels is now recognized to contribute to the physiopathology of hypertension. This review speculates that inflammation represents a mediator between hypertension and neurodegenerative diseases, either by a decrease in cerebral blood flow or a disruption of the blood-brain barrier which will, in turn, let inflammatory cells and neurotoxic molecules enter the brain parenchyma. This may impact brain functions including cognition and contribute to neurodegenerative diseases. This review will thus discuss the relationship between hypertension, systemic inflammation, cerebrovascular functions, neuroinflammation, and brain dysfunctions. The potential clinical future of immunotherapies against hypertension and associated cerebrovascular risks will also be presented.
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Affiliation(s)
- Jessica Youwakim
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
- Centre interdisciplinaire de recherche sur le cerveau et l’apprentissage (CIRCA); Montreal, QC, Canada
- Groupe de Recherche sur le Système Nerveux Central, Montreal, QC, Canada
| | - Hélène Girouard
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
- Centre interdisciplinaire de recherche sur le cerveau et l’apprentissage (CIRCA); Montreal, QC, Canada
- Groupe de Recherche sur le Système Nerveux Central, Montreal, QC, Canada
- Centre de recherche de l’Institut Universitaire de Gériaterie de Montréal, Montreal, QC, Canada
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17
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Oz M, Lorke DE, Kabbani N. A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor. Pharmacol Ther 2021; 221:107750. [PMID: 33275999 PMCID: PMC7854082 DOI: 10.1016/j.pharmthera.2020.107750] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023]
Abstract
The recent emergence of coronavirus disease-2019 (COVID-19) as a global pandemic has prompted scientists to address an urgent need for defining mechanisms of disease pathology and treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, employs angiotensin converting enzyme 2 (ACE2) as its primary target for cell surface attachment and likely entry into the host cell. Thus, understanding factors that may regulate the expression and function of ACE2 in the healthy and diseased body is critical for clinical intervention. Over 66% of all adults in the United States are currently using a prescription drug and while earlier findings have focused on possible upregulation of ACE2 expression through the use of renin angiotensin system (RAS) inhibitors, mounting evidence suggests that various other widely administered drugs used in the treatment of hypertension, heart failure, diabetes mellitus, hyperlipidemias, coagulation disorders, and pulmonary disease may also present a varied risk for COVID-19. Specifically, we summarize mechanisms on how heparin, statins, steroids and phytochemicals, besides their established therapeutic effects, may also interfere with SARS-CoV-2 viral entry into cells. We also describe evidence on the effect of several vitamins, phytochemicals, and naturally occurring compounds on ACE2 expression and activity in various tissues and disease models. This comprehensive review aims to provide a timely compendium on the potential impact of commonly prescribed drugs and pharmacologically active compounds on COVID-19 pathology and risk through regulation of ACE2 and RAS signaling.
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Key Words
- adam17, a disintegrin and metalloprotease 17
- ace, angiotensin i converting enzyme
- ace-inh., angiotensin i converting enzyme inhibitor
- ampk, amp-activated protein kinase
- ang-ii, angiotensin ii
- arb, angiotensin ii type 1-receptor blocker
- ards, acute respiratory distress syndrome
- at1-r, angiotensin ii type 1-receptor
- βarb, β-adrenergic receptor blockers
- bk, bradykinin
- ccb, calcium channel blockers
- ch25h, cholesterol-25-hydroxylase
- copd, chronic obstructive lung disease
- cox, cyclooxygenase
- covid-19, coronavirus disease-2019
- dabk, [des-arg9]-bradykinin
- erk, extracellular signal-regulated kinase
- 25hc, 25-hydroxycholesterol
- hs, heparan sulfate
- hspg, heparan sulfate proteoglycan
- ibd, inflammatory bowel disease
- map, mitogen-activated protein
- mers, middle east respiratory syndrome
- mrb, mineralocorticoid receptor blocker
- nos, nitric oxide synthase
- nsaid, non-steroid anti-inflammatory drug
- ras, renin-angiotensin system
- sars-cov, severe acute respiratory syndrome coronavirus
- sh, spontaneously hypertensive
- s protein, spike protein
- sirt1, sirtuin 1
- t2dm, type 2 diabetes mellitus
- tcm, traditional chinese medicine
- tmprss2, transmembrane protease, serine 2
- tnf, tumor necrosis factor
- ufh, unfractionated heparin
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Affiliation(s)
- Murat Oz
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait.
| | - Dietrich Ernst Lorke
- Department of Anatomy and Cellular Biology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates; Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Nadine Kabbani
- School of Systems Biology, George Mason University, Fairfax, VA 22030, USA
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18
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Kangussu LM, Melo-Braga MN, de Souza Lima BS, Santos RAS, de Andrade HM, Campagnole-Santos MJ. Angiotensin-(1-7) Central Mechanisms After ICV Infusion in Hypertensive Transgenic (mRen2)27 Rats. Front Neurosci 2021; 15:624249. [PMID: 33967677 PMCID: PMC8102993 DOI: 10.3389/fnins.2021.624249] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 03/30/2021] [Indexed: 11/14/2022] Open
Abstract
Previous data showed hypertensive rats subjected to chronic intracerebroventricular (ICV) infusion of angiotensin-(1-7) presented attenuation of arterial hypertension, improvement of baroreflex sensitivity, restoration of cardiac autonomic balance and a shift of cardiac renin-angiotensin system (RAS) balance toward Ang-(1-7)/Mas receptor. In the present study, we investigated putative central mechanisms related to the antihypertensive effect induced by ICV Ang-(1-7), including inflammatory mediators and the expression/activity of the RAS components in hypertensive rats. Furthermore, we performed a proteomic analysis to evaluate differentially regulated proteins in the hypothalamus of these animals. For this, Sprague Dawley (SD) and transgenic (mRen2)27 hypertensive rats (TG) were subjected to 14 days of ICV infusion with Ang-(1-7) (200 ng/h) or 0.9% sterile saline (0.5 μl/h) through osmotic mini-pumps. We observed that Ang-(1-7) treatment modulated inflammatory cytokines by decreasing TNF-α levels while increasing the anti-inflammatory IL-10. Moreover, we showed a reduction in ACE activity and gene expression of AT1 receptor and iNOS. Finally, our proteomic evaluation suggested an anti-inflammatory mechanism of Ang-(1-7) toward the ROS modulators Uchl1 and Prdx1.
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Affiliation(s)
- Lucas M Kangussu
- National Institute of Science and Technology in Nanobiopharmaceutics (INCT-Nanobiofar), Federal University of Minas Gerais, Belo Horizonte, Brazil.,Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Marcella Nunes Melo-Braga
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Robson A S Santos
- National Institute of Science and Technology in Nanobiopharmaceutics (INCT-Nanobiofar), Federal University of Minas Gerais, Belo Horizonte, Brazil.,Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Maria José Campagnole-Santos
- National Institute of Science and Technology in Nanobiopharmaceutics (INCT-Nanobiofar), Federal University of Minas Gerais, Belo Horizonte, Brazil.,Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
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19
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Oz M, Lorke DE. Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury. Biomed Pharmacother 2021; 136:111193. [PMID: 33461019 PMCID: PMC7836742 DOI: 10.1016/j.biopha.2020.111193] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/15/2020] [Accepted: 12/26/2020] [Indexed: 12/11/2022] Open
Abstract
The recent emergence of coronavirus disease-2019 (COVID-19) as a pandemic affecting millions of individuals has raised great concern throughout the world, and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the causative agent for COVID-19. The multifunctional protein angiotensin converting enzyme 2 (ACE2) is accepted as its primary target for entry into host cells. In its enzymatic function, ACE2, like its homologue ACE, regulates the renin-angiotensin system (RAS) critical for cardiovascular and renal homeostasis in mammals. Unlike ACE, however, ACE2 drives an alternative RAS pathway by degrading Ang-II and thus operates to balance RAS homeostasis in the context of hypertension, heart failure, and cardiovascular as well as renal complications of diabetes. Outside the RAS, ACE2 hydrolyzes key peptides, such as amyloid-β, apelin, and [des-Arg9]-bradykinin. In addition to its enzymatic functions, ACE2 is found to regulate intestinal amino acid homeostasis and the gut microbiome. Although the non-enzymatic function of ACE2 as the entry receptor for SARS-CoV-2 has been well established, the contribution of enzymatic functions of ACE2 to the pathogenesis of COVID-19-related lung injury has been a matter of debate. A complete understanding of this central enzyme may begin to explain the various symptoms and pathologies seen in SARS-CoV-2 infected individuals, and may aid in the development of novel treatments for COVID-19.
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Affiliation(s)
- Murat Oz
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait.
| | - Dietrich Ernst Lorke
- Department of Anatomy and Cellular Biology, Khalifa University, Abu Dhabi, United Arab Emirates; Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
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20
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Woods C, Marques-Lopes J, Contoreggi NH, Milner TA, Pickel VM, Wang G, Glass MJ. Tumor Necrosis Factor α Receptor Type 1 Activation in the Hypothalamic Paraventricular Nucleus Contributes to Glutamate Signaling and Angiotensin II-Dependent Hypertension. J Neurosci 2021; 41:1349-1362. [PMID: 33303682 PMCID: PMC7888211 DOI: 10.1523/jneurosci.2360-19.2020] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 11/06/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022] Open
Abstract
There are significant neurogenic and inflammatory influences on blood pressure, yet the role played by each of these processes in the development of hypertension is unclear. Tumor necrosis factor α (TNFα) has emerged as a critical modulator of blood pressure and neural plasticity; however, the mechanism by which TNFα signaling contributes to the development of hypertension is uncertain. We present evidence that following angiotensin II (AngII) infusion the TNFα type 1 receptor (TNFR1) plays a key role in heightened glutamate signaling in the hypothalamic paraventricular nucleus (PVN), a key central coordinator of blood pressure control. Fourteen day administration of a slow-pressor dose of AngII in male mice was associated with transcriptional and post-transcriptional (increased plasma membrane affiliation) regulation of TNFR1 in the PVN. Further, TNFR1 was shown to be critical for elevated NMDA-mediated excitatory currents in sympathoexcitatory PVN neurons following AngII infusion. Finally, silencing PVN TNFR1 prevented the increase in systolic blood pressure induced by AngII. These findings indicate that TNFR1 modulates a cellular pathway involving an increase in NMDA-mediated currents in the PVN following AngII infusion, suggesting a mechanism whereby TNFR1 activation contributes to hypertension via heightened hypothalamic glutamate-dependent signaling.SIGNIFICANCE STATEMENT Inflammation is critical for the emergence of hypertension, yet the mechanisms by which inflammatory mediators contribute to this dysfunction are not clearly defined. We show that tumor necrosis factor α receptor 1 (TNFR1) in the paraventricular hypothalamic nucleus (PVN), a critical neuroregulator of cardiovascular function, plays an important role in the development of hypertension in mice. In the PVN, TNFR1 expression and plasma membrane localization are upregulated during hypertension induced by angiotensin II (AngII). Further, TNFR1 activation was essential for NMDA signaling and the heightening NMDA currents during hypertension. Finally, TNFR1 silencing in the PVN inhibits elevated blood pressure induced by AngII. These results point to a critical role for hypothalamic TNFR1 signaling in hypertension.
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Affiliation(s)
- Clara Woods
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065
| | - Jose Marques-Lopes
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065
| | - Natalina H Contoreggi
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065
| | - Teresa A Milner
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065
- Harold and Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065
| | - Virginia M Pickel
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065
| | - Gang Wang
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065
| | - Michael J Glass
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10065
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21
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Molina-Van den Bosch M, Jacobs-Cachá C, Vergara A, Serón D, Soler MJ. [The renin-angiotensin system and the brain]. HIPERTENSION Y RIESGO VASCULAR 2021; 38:125-132. [PMID: 33526381 DOI: 10.1016/j.hipert.2020.12.001] [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: 08/17/2020] [Revised: 12/14/2020] [Accepted: 12/20/2020] [Indexed: 12/17/2022]
Abstract
The renin-angiotensin-aldosterone (RAAS) system and its effects on blood pressure and the regulation of water and electrolyte balance have been studied focusing on the cardiovascular and renal system. The activation of RAAS in other organs has local and systemic repercussions by modeling the macro- and microvasculture of peripheral organs. The brain RAAS influence on systemic blood pressure through the sympathetic nervous system. The angiotensin converting enzyme/angiotensin II/angiotensin 1 receptor axis (ACE/AngII/AT1), classical pathway, and angiotensin converting enzyme type 2/angiotensin (1-7)/Mas receptor (ACE2/Ang (1-7)/MasR), non-classical pathway, are involved in the modulation of the sympathetic response. The imbalance of these two axes with subsequently Ang II accumulation promote neurogenic hypertension and other vascular pathologies. The aminopeptidase/angiotensin IV/angiotensin 4 receptor (AMN/Ang IV/AT4) axis, which is exclusive of the brain, acts on cerebral microvasculature and participates in cognition, memory, and learning. The aim of this review is to decipher the major central RAAS mechanisms involved in blood pressure regulation. In addition, paracrine functions of brain RAAS and its role in neuroprotection and cognition are also described in this review.
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Affiliation(s)
- M Molina-Van den Bosch
- Grup de Nefrología, Vall d'Hebron Institut de Recerca (VHIR), Servei de Nefrología, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital, Barcelona, España
| | - C Jacobs-Cachá
- Grup de Nefrología, Vall d'Hebron Institut de Recerca (VHIR), Servei de Nefrología, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital, Barcelona, España
| | - A Vergara
- Grup de Nefrología, Vall d'Hebron Institut de Recerca (VHIR), Servei de Nefrología, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital, Barcelona, España
| | - D Serón
- Grup de Nefrología, Vall d'Hebron Institut de Recerca (VHIR), Servei de Nefrología, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital, Barcelona, España
| | - M J Soler
- Grup de Nefrología, Vall d'Hebron Institut de Recerca (VHIR), Servei de Nefrología, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital, Barcelona, España.
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22
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Gao HL, Yu XJ, Liu KL, Zuo YY, Fu LY, Chen YM, Zhang DD, Shi XL, Qi J, Li Y, Yi QY, Tian H, Wang XM, Yu JY, Zhu GQ, Liu JJ, Kang KB, Kang YM. Chronic Infusion of Astaxanthin Into Hypothalamic Paraventricular Nucleus Modulates Cytokines and Attenuates the Renin-Angiotensin System in Spontaneously Hypertensive Rats. J Cardiovasc Pharmacol 2021; 77:170-181. [PMID: 33538532 DOI: 10.1097/fjc.0000000000000953] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 10/28/2020] [Indexed: 11/26/2022]
Abstract
ABSTRACT Oxidative stress, the renin-angiotensin system (RAS), and inflammation are some of the mechanisms involved in the pathogenesis of hypertension. The aim of this study is to examine the protective effect of the chronic administration of astaxanthin, which is extracted from the shell of crabs and shrimps, into hypothalamic paraventricular nucleus (PVN) in spontaneously hypertensive rats. Animals were randomly assigned to 2 groups and treated with bilateral PVN infusion of astaxanthin or vehicle (artificial cerebrospinal fluid) through osmotic minipumps (Alzet Osmotic Pumps, Model 2004, 0.25 μL/h) for 4 weeks. Spontaneously hypertensive rats had higher mean arterial pressure and plasma level of norepinephrine and proinflammatory cytokine; higher PVN levels of reactive oxygen species, NOX2, NOX4, IL-1β, IL-6, ACE, and AT1-R; and lower PVN levels of IL-10 and Cu/Zn SOD, Mn SOD, ACE2, and Mas receptors than Wistar-Kyoto rats. Our data showed that chronic administration of astaxanthin into PVN attenuated the overexpression of reactive oxygen species, NOX2, NOX4, inflammatory cytokines, and components of RAS within the PVN and suppressed hypertension. The present results revealed that astaxanthin played a role in the brain. Our findings demonstrated that astaxanthin had protective effect on hypertension by improving the balance between inflammatory cytokines and components of RAS.
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Affiliation(s)
- Hong-Li Gao
- 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 Education Ministry of China, Xi'an, China
| | - 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 Education Ministry of China, 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 Education Ministry of China, Xi'an, China
| | - Yi-Yi Zuo
- College of Stomatology, Xi'an Jiaotong University, Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Xi'an, Shaanxi, People's Republic of 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 Education Ministry of China, Xi'an, China
| | - Yan-Mei Chen
- 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 Education Ministry of China, Xi'an, China
| | - Dong-Dong Zhang
- 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 Education Ministry of China, Xi'an, China
| | - Xiao-Lian Shi
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 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 Education Ministry of China, 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 Education Ministry of China, Xi'an, China
| | - Qiu-Yue Yi
- 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 Education Ministry of China, Xi'an, China
| | - Hua Tian
- 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 Education Ministry of China, Xi'an, China
| | - Xiao-Min Wang
- 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 Education Ministry of China, Xi'an, China
| | - Jia-Yue 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 Education Ministry of China, Xi'an, China
| | - Guo-Qing Zhu
- Department of Physiology, Nanjing Medical University, Nanjing, China; and
| | - Jin-Jun 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 Education Ministry of China, Xi'an, China
| | - Kai B Kang
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL
| | - 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 Education Ministry of China, Xi'an, China
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23
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Wei SG, Yu Y, Felder RB. TNF-α-induced sympathetic excitation requires EGFR and ERK1/2 signaling in cardiovascular regulatory regions of the forebrain. Am J Physiol Heart Circ Physiol 2021; 320:H772-H786. [PMID: 33337962 PMCID: PMC8082799 DOI: 10.1152/ajpheart.00606.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 12/09/2020] [Accepted: 12/09/2020] [Indexed: 12/13/2022]
Abstract
Peripherally or centrally administered TNF-α elicits a prolonged sympathetically mediated pressor response, but the underlying molecular mechanisms are unknown. Activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in cardiovascular regions of the brain has recently been recognized as a key mediator of sympathetic excitation, and ERK1/2 signaling is induced by activation of epidermal growth factor receptor (EGFR) tyrosine kinase activity. The present study examined the role of EGFR and ERK1/2 signaling in the sympathetic response to TNF-α. In urethane-anesthetized rats, intracarotid artery injection of TNF-α increased phosphorylation of EGFR and ERK1/2 in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN); upregulated the gene expression of excitatory mediators in SFO and PVN; and increased blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA). A continuous intracerebroventricular infusion of the selective EGFR tyrosine kinase inhibitor AG1478 or the ERK1/2 inhibitor PD98059 significantly attenuated these responses. Bilateral PVN microinjections of TNF-α also increased phosphorylated ERK1/2 and the gene expression of excitatory mediators in PVN, along with increases in BP, HR, and RSNA, and these responses were substantially reduced by prior bilateral PVN microinjections of AG1478. These results identify activation of EGFR in cardiovascular regulatory regions of the forebrain as an important molecular mediator of TNF-α-driven sympatho-excitatory responses and suggest that EGFR activation of the ERK1/2 signaling pathway plays an essential role. These mechanisms likely contribute to sympathetic excitation in pathophysiological states like heart failure and hypertension, in which circulating and brain TNF-α levels are increased.NEW & NOTEWORTHY Proinflammatory cytokines contribute to the augmented sympathetic nerve activity in hypertension and heart failure, but the central mechanisms involved are largely unknown. The present study reveals that TNF-α transactivates EGFR in the subfornical organ and the hypothalamic paraventricular nucleus to initiate ERK1/2 signaling, upregulate the gene expression of excitatory mediators, and increase sympathetic nerve activity. These findings identify EGFR as a gateway to sympathetic excitation and a potential target for intervention in cardiovascular disease states.
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Affiliation(s)
- Shun-Guang Wei
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
- Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa
- Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Yang Yu
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Robert B Felder
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
- Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa
- Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa
- Veterans Affairs Medical Center, Iowa City, Iowa
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24
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Kaur U, Acharya K, Mondal R, Singh A, Saso L, Chakrabarti S, Chakrabarti SS. Should ACE2 be given a chance in COVID-19 therapeutics: A semi-systematic review of strategies enhancing ACE2. Eur J Pharmacol 2020; 887:173545. [PMID: 32926917 PMCID: PMC7485553 DOI: 10.1016/j.ejphar.2020.173545] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/05/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022]
Abstract
The severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) has resulted in almost 28 million cases of COVID-19 (Corona virus disease-2019) and more than 900000 deaths worldwide since December 2019. In the absence of effective antiviral therapy and vaccine, treatment of COVID-19 is largely symptomatic. By making use of its spike (S) protein, the virus binds to its primary human cell receptor, angiotensin converting enzyme 2 (ACE2) which is present in the pulmonary epithelial cells as well as other organs. SARS-CoV-2 may cause a downregulation of ACE2. ACE2 plays a protective role in the pulmonary system through its Mas-receptor and alamandine-MrgD-TGR7 pathways. Loss of this protective effect could be a major component of COVID-19 pathogenesis. An attractive strategy in SARS-CoV-2 therapeutics would be to augment ACE2 either directly by supplementation or indirectly through drugs which increase its levels or stimulate its downstream players. In this semi-systematic review, we have analysed the pathophysiological interplay between ACE and ACE2 in the cardiopulmonary system, the modulation of these two proteins by SARS-CoV-2, and potential therapeutic avenues targeting ACE-Ang II and ACE2-Ang (1-7) axes, that can be utilized against COVID-19 disease progression.
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Affiliation(s)
- Upinder Kaur
- Department of Pharmacology, All India Institute of Medical Sciences, Gorakhpur, UP, India
| | - Kumudini Acharya
- Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, UP, India
| | - Ritwick Mondal
- Department of Internal Medicine, Institute of Post Graduate Medical Education and Research, Kolkata, WB, India
| | - Amit Singh
- Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, UP, India
| | - Luciano Saso
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Sasanka Chakrabarti
- Department of Biochemistry and Central Research Cell, Maharishi Markandeshwar (deemed to be) University, Mullana, Ambala, Haryana, India.
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25
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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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26
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Salt-dependent hypertension and inflammation: targeting the gut-brain axis and the immune system with Brazilian green propolis. Inflammopharmacology 2020; 28:1163-1182. [PMID: 32785827 PMCID: PMC8826348 DOI: 10.1007/s10787-020-00742-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 07/30/2020] [Indexed: 01/22/2023]
Abstract
Systemic arterial hypertension (SAH) is a major health problem around the world and its development has been associated with exceeding salt consumption by the modern society. The mechanisms by which salt consumption increase blood pressure (BP) involve several homeostatic systems but many details have not yet been fully elucidated. Evidences accumulated over the last 60 decades raised the involvement of the immune system in the hypertension development and opened a range of possibilities for new therapeutic targets. Green propolis is a promising natural product with potent anti-inflammatory properties acting on specific targets, most of them participating in the gut-brain axis of the sodium-dependent hypertension. New anti-hypertensive products reinforce the therapeutic arsenal improving the corollary of choices, especially in those cases where patients are resistant or refractory to conventional therapy. This review sought to bring the newest advances in the field articulating evidences that show a cross-talking between inflammation and the central mechanisms involved with the sodium-dependent hypertension as well as the stablished actions of green propolis and some of its biologically active compounds on the immune cells and cytokines that would be involved with its anti-hypertensive properties.
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27
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Xue B, Zhang Y, Johnson AK. Interactions of the Brain Renin-Angiotensin-System (RAS) and Inflammation in the Sensitization of Hypertension. Front Neurosci 2020; 14:650. [PMID: 32760236 PMCID: PMC7373760 DOI: 10.3389/fnins.2020.00650] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 05/26/2020] [Indexed: 01/07/2023] Open
Abstract
Mounting evidence indicates that the renin-angiotensin (RAS) and immune systems interact with one another in the central nervous system (CNS) and that they are importantly involved in the pathogenesis of hypertension. Components comprising the classic RAS were first identified in the periphery, and subsequently, similar factors were found to be generated de novo in many different organs including the brain. There is humoral-neural coupling between the systemic and brain RASs, which is important for controlling sympathetic tone and the release of endocrine factors that collectively determine blood pressure (BP). Similar to the interactions between the systemic and brain RASs is the communication between the peripheral and brain immune systems. Systemic inflammation activates the brain’s immune response. Importantly, the RAS and inflammatory factors act synergistically in brain regions involved in the regulation of BP. This review presents evidence of how such interactions between the brain RAS and central immune mechanisms contribute to the pathogenesis of hypertension. Emphasis focuses on the role of these interactions to induce neuroplastic changes in a central neural network resulting in hypertensive response sensitization (HTRS). Neuroplasticity and HTRS can be induced by challenges (stressors) presented earlier in life such as a low-dose of angiotensin II or high fat diet (HFD) feeding in adults. Similarly, the offspring of mothers with gestational hypertension or of mothers ingesting a HFD during pregnancy are reprogrammed and manifest HTRS when exposed to new stressors as adults. Consideration of the actions and interactions of the brain RAS and inflammatory mediators in the context of the induction and expression of HTRS will provide insights into the etiology of high BP that may lead to new strategies for the prevention and treatment of hypertension.
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Affiliation(s)
- Baojian Xue
- Department of Psychological and Brain Sciences, The University of Iowa, Iowa City, IA, United States
| | - Yuping Zhang
- Department of Pathophysiology, Hebei North University, Zhangjiakou, China
| | - Alan Kim Johnson
- Department of Psychological and Brain Sciences, The University of Iowa, Iowa City, IA, United States.,Neuroscience and Pharmacology, The University of Iowa, Iowa City, IA, United States.,Health and Human Physiology, The University of Iowa, Iowa City, IA, United States.,The François M. Abboud Cardiovascular Research Center, The University of Iowa, Iowa City, IA, United States
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28
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Elsaafien K, de Kloet AD, Krause EG, Sumners C. Brain Angiotensin Type-1 and Type-2 Receptors in Physiological and Hypertensive Conditions: Focus on Neuroinflammation. Curr Hypertens Rep 2020; 22:48. [PMID: 32661792 PMCID: PMC7780348 DOI: 10.1007/s11906-020-01062-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE OF REVIEW To review recent data that suggest opposing effects of brain angiotensin type-1 (AT1R) and type-2 (AT2R) receptors on blood pressure (BP). Here, we discuss recent studies that suggest pro-hypertensive and pro-inflammatory actions of AT1R and anti-hypertensive and anti-inflammatory actions of AT2R. Further, we propose mechanisms for the interplay between brain angiotensin receptors and neuroinflammation in hypertension. RECENT FINDINGS The renin-angiotensin system (RAS) plays an important role in regulating cardiovascular physiology. This includes brain AT1R and AT2R, both of which are expressed in or adjacent to brain regions that control BP. Activation of AT1R within those brain regions mediate increases in BP and cause neuroinflammation, which augments the BP increase in hypertension. The fact that AT1R and AT2R have opposing actions on BP suggests that AT1R and AT2R may have similar opposing actions on neuroinflammation. However, the mechanisms by which brain AT1R and AT2R mediate neuroinflammatory responses remain unclear. The interplay between brain angiotensin receptor subtypes and neuroinflammation exacerbates or protects against hypertension.
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Affiliation(s)
- Khalid Elsaafien
- Department of Pharmacodynamics, University of Florida College of Pharmacy, Gainesville, FL, USA
| | - Annette D de Kloet
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA
- Center for Integrative Cardiovascular and Metabolic Diseases, University of Florida, Gainesville, FL, USA
- Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Eric G Krause
- Department of Pharmacodynamics, University of Florida College of Pharmacy, Gainesville, FL, USA
- Center for Integrative Cardiovascular and Metabolic Diseases, University of Florida, Gainesville, FL, USA
- Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Colin Sumners
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA.
- Center for Integrative Cardiovascular and Metabolic Diseases, University of Florida, Gainesville, FL, USA.
- Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
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29
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TNF-α inhibition decreases MMP-2 activity, reactive oxygen species formation and improves hypertensive vascular hypertrophy independent of its effects on blood pressure. Biochem Pharmacol 2020; 180:114121. [PMID: 32592722 DOI: 10.1016/j.bcp.2020.114121] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/28/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023]
Abstract
Systemic arterial hypertension is a public health problem associated with an increased risk of cardiovascular disease. Matrix metalloproteinases (MMP) are endopeptidases that participate in hypertension-induced cardiovascular remodeling, which may be activated by oxidative stress. Angiotensin II (Ang II), a potent hypertrophic and vasoconstrictor peptide, increases oxidative stress, MMP-2 activity and tumor necrosis factor (TNF-α) expression. In vitro studies have shown that TNF-α is essential for Ang II-induced MMP-2 expression. Thus, this study evaluated whetherTNF-α inhibition decreases the development of hypertension-induced vascular remodeling via reduction of MMP-2 activity and reactive oxygen species (ROS) formation. Two distinct pharmacological approaches were used in the present study: Pentoxifylline (PTX), a non-selective inhibitor of phosphodiesterases that exerts anti- inflammatory effects via inhibition of TNF-α, and Etanercept (ETN), a selective TNF-α inhibitor. 2-kidney and 1-Clip (2K1C). 2-kidney and 1-Clip (2K1C) and Sham rats were treated with Vehicle, PTX (50 mg/Kg and 100 mg/kg daily) or ETN (0.3 mg/Kg and 1 mg/kg; three times per week). Systolic blood pressure (SBP) was measured weekly by tail cuff plethysmography. Plasma TNF-α and IL-1β levels were evaluated by enzyme-linked immunosorbent assay (ELISA) technique. The vascular hypertrophy was examined in the aorta sections stained with hematoxylin/eosin. ROS in aortas was evaluated by dihydroethidium and chemiluminescence lucigenin assay. Aortic MMP-2 levels and activity were evaluated by gel zymography and in situ zymography, respectively. The 2K1C animals showed a progressive increase in SBP levels and was accompanied by significant vascular hypertrophy (p < 0.05 vs Sham). Treatment with PTX at higher doses decreased SBP and vascular remodeling in 2K1C animals (p < 0.05 vs 2K1C vehicle). Although the highest dose of ETN treatment did not reduce blood pressure, the vascular hypertrophy was significantly attenuated in 2K1C animals treated with ETN1 (p < 0.05). The increased cytokine levels and ROS formation were reversed by the highest doses of both PTX and ETN. The increase in MMP-2 levels and activity in 2K1C animals were reduced by PTX100 and ETN1 treatments (p < 0.05 vs vehicle 2K1C). Lower doses of PTX and ETN did not affect any of the evaluated parameters in this study, except for a small reduction in TNF-α levels. The findings of the present study suggest that PTX and ETN treatment exerts immunomodulatory effects, blunted excessive ROS formation, and decreased renovascular hypertension-induced MMP-2 up-regulation, leading to improvement ofvascular remodeling typically found in 2K1C hypertension. Therefore, strategies using anti-hypertensive drugs in combination with TNF alpha inhibitors could be an attractive therapeutic approach to tackle hypertension and its associated vascular remodeling.
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Yang J, Wang M, Wang S, Li G, Gao Y. Study on ferroptosis pathway that operates in hypertensive brain damage. Clin Exp Hypertens 2020; 42:748-752. [PMID: 32564622 DOI: 10.1080/10641963.2020.1783545] [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: 01/20/2023]
Abstract
OBJECTIVE This study aimed to explore the mechanism of hypertensive brain damage from ferroptosis pathway. METHODS Ten 22-week-old SHR rats were labeled as hypertension group(HBP), while ten WKY rats of comparable age, weight were used as normal blood pressure group(NBP). After 2 weeks of feeding, hypertensive brain damage was observed by comparing the pathological changes of brain tissue in SHR rats and WKY rats. Furthermore, the expression of GPX4 in the cerebral cortex was detected by immunofluorescence. The content of GSH was determined by spectrophotometer. The content of iron was detected by ferrous chromite colorimetry. And the content of MDA was determined by spectrophotometer. Compare the difference to investigate the role of ferroptosis mechanism in hypertensive brain damage. RESULTS Brain damage occurred in 24-week-old SHR rats compared with WKY rats. In the HBP, the GPX4 and GSH were significantly lower than those in the NBP, and the total iron content and MDA were significantly increased. CONCLUSION Thses findings suggest ferroptosis is closely related to hypertensive brain damage. Elevated blood pressure leads to iron overload in the brain. Excessive iron increases oxidative stress and lipid peroxidation in the brain, and eventually causes brain damage.
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Affiliation(s)
- Jian Yang
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine , Tianjin, China
| | - Min Wang
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine , Tianjin, China
| | - Shu Wang
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine , Tianjin, China
| | - Guiping Li
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine , Tianjin, China
| | - Ying Gao
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine , Tianjin, China
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Zhang DD, Liang YF, Qi J, Kang KB, Yu XJ, Gao HL, Liu KL, Chen YM, Shi XL, Xin GR, Fu LY, Kang YM, Cui W. Carbon Monoxide Attenuates High Salt-Induced Hypertension While Reducing Pro-inflammatory Cytokines and Oxidative Stress in the Paraventricular Nucleus. Cardiovasc Toxicol 2020; 19:451-464. [PMID: 31037602 DOI: 10.1007/s12012-019-09517-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Carbon monoxide (CO) presents anti-inflammatory and antioxidant activities as a new gaseous neuromessenger produced by heme oxygenase-1 (HO-1) in the body. High salt-induced hypertension is relevant to the levels of pro-inflammatory cytokines (PICs) and oxidative stress in the hypothalamic paraventricular nucleus (PVN). We explored whether CO in PVN can attenuate high salt-induced hypertension by regulating PICs or oxidative stress. Male Dahl Salt-Sensitive rats were fed high-salt (8% NaCl) or normal-salt (0.3% NaCl) diet for 4 weeks. CORM-2, ZnPP IX, or vehicle was microinjected into bilateral PVN for 6 weeks. High-salt diet increased the levels of MAP, plasma norepinephrine (NE), reactive oxygen species (ROS), and the expressions of COX2, IL-1β, IL-6, NOX2, and NOX4 significantly in PVN (p < 0.05), but decreased the expressions of HO-1 and Cu/Zn-SOD in PVN (p < 0.05). Salt increased sympathetic activity as measured by circulating norepinephrine, and increased the ratio of basal RSNA to max RSNA, in part by decreasing max RSNA. PVN microinjection of CORM-2 decreased the levels of MAP, NE, RSNA, ROS and the expressions of COX2, IL-1β, IL-6, NOX2, NOX4 significantly in PVN of hypertensive rat (p < 0.05), but increased the expressions of HO-1 and Cu/Zn-SOD significantly (p < 0.05), which were all opposite to the effects of ZnPP IX microinjected in PVN (p < 0.05). We concluded that exogenous or endogenous CO attenuates high salt-induced hypertension by regulating PICs and oxidative stress in PVN.
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Affiliation(s)
- Dong-Dong Zhang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710061, China.,Department of Anatomy, School of Basic Medical Sciences, Jiamusi University, Jiamusi, 154007, China
| | - Yan-Feng Liang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710061, China.,Department of Pathophysiology, School of Basic Medical Sciences, Jiamusi University, Jiamusi, 154007, China
| | - Jie Qi
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Kai B Kang
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Xiao-Jing Yu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Hong-Li Gao
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Kai-Li Liu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yan-Mei Chen
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xiao-Lian Shi
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Guo-Rui Xin
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Li-Yan Fu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yu-Ming Kang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Wei Cui
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
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Worker CJ, Li W, Feng CY, Souza LAC, Gayban AJB, Cooper SG, Afrin S, Romanick S, Ferguson BS, Feng Earley Y. The neuronal (pro)renin receptor and astrocyte inflammation in the central regulation of blood pressure and blood glucose in mice fed a high-fat diet. Am J Physiol Endocrinol Metab 2020; 318:E765-E778. [PMID: 32228320 PMCID: PMC7272727 DOI: 10.1152/ajpendo.00406.2019] [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] [Indexed: 12/11/2022]
Abstract
We report here that the neuronal (pro)renin receptor (PRR), a key component of the brain renin-angiotensin system (RAS), plays a critical role in the central regulation of high-fat-diet (HFD)-induced metabolic pathophysiology. The neuronal PRR is known to mediate formation of the majority of angiotensin (ANG) II, a key bioactive peptide of the RAS, in the central nervous system and to regulate blood pressure and cardiovascular function. However, little is known about neuronal PRR function in overnutrition-related metabolic physiology. Here, we show that PRR deletion in neurons reduces blood pressure, neurogenic pressor activity, and fasting blood glucose and improves glucose tolerance without affecting food intake or body weight following a 16-wk HFD. Mechanistically, we found that a HFD increases levels of the PRR ligand (pro)renin in the circulation and hypothalamus and of ANG II in the hypothalamus, indicating activation of the brain RAS. Importantly, PRR deletion in neurons reduced astrogliosis and activation of the astrocytic NF-κB p65 (RelA) in the arcuate nucleus and the ventromedial nucleus of the hypothalamus. Collectively, our findings indicate that the neuronal PRR plays essential roles in overnutrition-related metabolic pathophysiology.
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Affiliation(s)
- Caleb J Worker
- Department of Pharmacology and Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, Reno, Nevada
- Center for Molecular and Cellular Signal Transduction in the Cardiovascular System, University of Nevada, Reno, Nevada
| | - Wencheng Li
- Department of Pathology, Wake Forest University, Winston-Salem, North Carolina
| | - Cheng-Yuan Feng
- Department of Neurology, Loma Linda University, Loma Linda, California
| | - Lucas A C Souza
- Department of Pharmacology and Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, Reno, Nevada
- Center for Molecular and Cellular Signal Transduction in the Cardiovascular System, University of Nevada, Reno, Nevada
| | - Ariana Julia B Gayban
- Department of Pharmacology and Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, Reno, Nevada
- Center for Molecular and Cellular Signal Transduction in the Cardiovascular System, University of Nevada, Reno, Nevada
| | - Silvana G Cooper
- Department of Pharmacology and Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, Reno, Nevada
- Center for Molecular and Cellular Signal Transduction in the Cardiovascular System, University of Nevada, Reno, Nevada
| | - Sanzida Afrin
- Department of Pharmacology and Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, Reno, Nevada
- Center for Molecular and Cellular Signal Transduction in the Cardiovascular System, University of Nevada, Reno, Nevada
| | - Samantha Romanick
- Center for Molecular and Cellular Signal Transduction in the Cardiovascular System, University of Nevada, Reno, Nevada
- Department of Neurology, Loma Linda University, Loma Linda, California
| | - Bradley S Ferguson
- Center for Molecular and Cellular Signal Transduction in the Cardiovascular System, University of Nevada, Reno, Nevada
- Department of Neurology, Loma Linda University, Loma Linda, California
| | - Yumei Feng Earley
- Department of Pharmacology and Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, Reno, Nevada
- Center for Molecular and Cellular Signal Transduction in the Cardiovascular System, University of Nevada, Reno, Nevada
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Welcome MO, Mastorakis NE. Stress-induced blood brain barrier disruption: Molecular mechanisms and signaling pathways. Pharmacol Res 2020; 157:104769. [PMID: 32275963 DOI: 10.1016/j.phrs.2020.104769] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 03/09/2020] [Accepted: 03/19/2020] [Indexed: 02/07/2023]
Abstract
Stress is a nonspecific response to a threat or noxious stimuli with resultant damaging consequences. Stress is believed to be an underlying process that can trigger central nervous system disorders such as depression, anxiety, and post-traumatic stress disorder. Though the pathophysiological basis is not completely understood, data have consistently shown a pivotal role of inflammatory mediators and hypothalamo-pituitary-adrenal (HPA) axis activation in stress induced disorders. Indeed emerging experimental evidences indicate a concurrent activation of inflammatory signaling pathways and not only the HPA axis, but also, peripheral and central renin-angiotensin system (RAS). Furthermore, recent experimental data indicate that the HPA and RAS are coupled to the signaling of a range of central neuro-transmitter, -mediator and -peptide molecules that are also regulated, at least in part, by inflammatory signaling cascades and vice versa. More recently, experimental evidences suggest a critical role of stress in disruption of the blood brain barrier (BBB), a neurovascular unit that regulates the movement of substances and blood-borne immune cells into the brain parenchyma, and prevents peripheral injury to the brain substance. However, the mechanisms underlying stress-induced BBB disruption are not exactly known. In this review, we summarize studies conducted on the effects of stress on the BBB and integrate recent data that suggest possible molecular mechanisms and signaling pathways underlying stress-induced BBB disruption. Key molecular targets and pharmacological candidates for treatment of stress and related illnesses are also summarized.
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Affiliation(s)
- Menizibeya O Welcome
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Nile University of Nigeria, Abuja, Nigeria.
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Xu ML, Yu XJ, Zhao JQ, Du Y, Xia WJ, Su Q, Du MM, Yang Q, Qi J, Li Y, Zhou SW, Zhu GQ, Li HB, Kang YM. Calcitriol ameliorated autonomic dysfunction and hypertension by down-regulating inflammation and oxidative stress in the paraventricular nucleus of SHR. Toxicol Appl Pharmacol 2020; 394:114950. [PMID: 32147540 DOI: 10.1016/j.taap.2020.114950] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 02/21/2020] [Accepted: 03/04/2020] [Indexed: 02/07/2023]
Abstract
The hypothalamic paraventricular nucleus (PVN) plays crucial roles in central cardiovascular regulation. Increasing evidence in humans and rodents shows that vitamin D intake is important for achieving optimal cardiovascular function. The purpose of this study was to investigate whether calcitriol, an active form of vitamin D, improves autonomic and cardiovascular function in hypertensive rats and whether PVN oxidative stress and inflammation are involved in these beneficial effects. Male spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were treated with either calcitriol (40 ng/day) or vehicle (0.11 μL/h) through chronic PVN infusion for 4 weeks. Blood pressure and heart rate were recorded continuously by radiotelemetry. PVN tissue, heart and plasma were collected for molecular and histological analysis. Compared to WKY rats, SHR exhibited increased systolic blood pressure, sympathetic drive, and cardiac hypertrophy and remodeling. These were associated with higher mRNA and protein expression levels of high mobility box 1 (HMGB1), receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), proinflammatory cytokines, NADPH oxidase subunit in the PVN. In addition, increased norepinephrine in plasma, elevated reactive oxygen species levels and activation of microglia in the PVN were also observed in SHR. Chronic calcitriol treatment ameliorated these changes but not in WKY rats. Our results demonstrate that chronic infusion of calcitriol in the PVN ameliorates hypertensive responses, sympathoexcitation and retains cardiovascular function in SHR. Reduced inflammation and oxidative stress within the PVN are involved in these calcitriol-induced effects.
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Affiliation(s)
- Meng-Lu Xu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China; Department of Nephrology, the First Affiliated Hospital of Xi'an Medical University, Xi'an 710003, China
| | - Xiao-Jing Yu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Jian-Qiang Zhao
- Department of Nephrology, the First Affiliated Hospital of Xi'an Medical University, Xi'an 710003, China
| | - Yan Du
- Department of Nephrology, the First Affiliated Hospital of Xi'an Medical University, Xi'an 710003, China
| | - Wen-Jie Xia
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Qing Su
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Meng-Meng Du
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Qing Yang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Jie Qi
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Ying Li
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Shao-Wen Zhou
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Guo-Qing Zhu
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029, China
| | - Hong-Bao Li
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China.
| | - Yu-Ming Kang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an Jiaotong University, Xi'an 710061, China.
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Systemic administration of pentoxifylline attenuates the development of hypertension in renovascular hypertensive rats. Hypertens Res 2020; 43:667-678. [PMID: 32060380 DOI: 10.1038/s41440-020-0412-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 12/17/2019] [Accepted: 01/19/2020] [Indexed: 12/14/2022]
Abstract
There is evidence to suggest that hypertension involves a chronic low-grade systemic inflammatory response; however, the underlying mechanisms are unclear. To further understand the role of inflammation in hypertension, we used a rat renovascular model of hypertension in which we administered the TNF-α synthesis inhibitor pentoxifylline (PTX, 30 mg/kg/day) in the drinking water for 60 days. In conscious rats, PTX administration significantly attenuated the development of hypertension (systolic blood pressure, PTX: 145 ± 8 vs. vehicle (Veh): 235 ± 11 mmHg, after 38 days of treatment, P < 0.05, N = 5/group). This attenuation in hypertension was coupled with a decrease in the low-frequency spectra of systolic blood pressure variability (PTX: 1.23 ± 0.2 vs Veh: 3.05 ± 0.8 arbitrary units, P < 0.05, N = 5/group). Furthermore, systemic PTX administration decreased c-Fos expression within the hypothalamic paraventricular nucleus (PTX: 17 ± 4 vs. Veh: 70 ± 13 cells, P < 0.01, N = 5, PVN) and increased the total number of microglial branches (PTX: 2129 ± 242 vs. Veh: 1415 ± 227 branches, P < 0.05, N = 4/group). Acute central injection of PTX (20 μg) under urethane anesthesia caused a small transient decrease in blood pressure but did not change renal sympathetic nerve activity. Surprisingly, we found no detectable basal levels of plasma TNF-α in either PTX- or vehicle-treated animals. These results suggest that inflammation plays a role in renovascular hypertension and that PTX might act both peripherally and centrally to prevent hypertension.
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Meng Q, Guo Y, Zhang D, Zhang Q, Li Y, Bian H. Tongsaimai reverses the hypertension and left ventricular remolding caused by abdominal aortic constriction in rats. JOURNAL OF ETHNOPHARMACOLOGY 2020; 246:112154. [PMID: 31415848 DOI: 10.1016/j.jep.2019.112154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 08/01/2019] [Accepted: 08/10/2019] [Indexed: 06/10/2023]
Abstract
Treating ventricular remodeling continues to be a clinical challenge. Studies have shown that hypertension is one of the most common causes of ventricular remodeling, and is a major cause of cardiovascular risk in adults. Here, we report that Tongsaimai (TSM), a Chinese traditional medicine, could inhibit arterial pressure and left ventricular pressure to improve hemodynamic abnormalities in rats impaired by abdominal aortic constriction (AAC). Administration of TSM significantly reduced the heart mass index and the left ventricular mass index significantly in AAC rats. TSM could also markedly ameliorate cardiac collagen deposition and reduce the concentration of hydroxyproline in the heart of AAC rats. Moreover, TSM alleviated cardiac histomorphology injury resulting from AAC, including reducing cardiomyocyte hypertrophy, fibrous connective tissue hyperplasia, cardiomyocyte apoptosis, replacement fibrosis and the disorders of myocardial myofibrils, intercalated discs, mitochondria and mitochondrial crista. In addition, the levels of transforming growth factor (TGF) - β and inflammation-related molecules including tumor necrosis factor-α (TNF-α), which were over-expressed with AAC, were decreased by STM. In conclusion, STM could reverse the hypertension and left ventricular remolding caused by abdominal aortic constriction in rats.
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Affiliation(s)
- Qinghai Meng
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
| | - Yao Guo
- Nanjing TechBoon Biotechnology Company Limited, Nanjing, Jiangsu, 211899, China.
| | - Dini Zhang
- Department of Environmental Protection, Nanjing Institute of Environmental Sciences, Nanjing, Jiangsu, 210042, China.
| | - Qichun Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
| | - Yu Li
- School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
| | - Huimin Bian
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
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Abstract
PURPOSE OF REVIEW To gather data from studies evaluating the pro-inflammatory profile of individuals with resistant hypertension (RH), and bring a clinical update of new and potential complementary therapies to treat inflammation in RH. RECENT FINDINGS Increases in pro-inflammatory cytokines are related to elevated blood pressure and target organ damage in RH patients. Clinical and experimental studies have shown that some biological therapies, especially TNF-α inhibitors, regulated pro- and anti-inflammatory cytokines associated with improvements in clinical outcomes, although they are not yet reported in RH. New emerging therapies to treat inflammation in RH, although promising, are still hypotheses that have not been scientifically confirmed in clinical trials. For this reason, inflammation-target treatments, such as the TNF-α and IL-6 inhibitors, should be encouraged for testing as complementary therapies in RH in order to elucidate their potential benefits.
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Yang T, Rodriguez V, Malphurs WL, Schmidt JT, Ahmari N, Sumners C, Martyniuk CJ, Zubcevic J. Butyrate regulates inflammatory cytokine expression without affecting oxidative respiration in primary astrocytes from spontaneously hypertensive rats. Physiol Rep 2019; 6:e13732. [PMID: 30039527 PMCID: PMC6056753 DOI: 10.14814/phy2.13732] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 05/07/2018] [Accepted: 05/09/2018] [Indexed: 01/16/2023] Open
Abstract
Neurons and glia exhibit metabolic imbalances in hypertensive animal models, and loss of metabolic homeostasis can lead to neuroinflammation and oxidative stress. The objective of this study was to determine the effects of the microbial metabolite butyrate on mitochondrial bioenergetics and inflammatory markers in mixed brainstem and hypothalamic primary cultures of astrocytes between normotensive (Sprague-Dawley, S-D) and spontaneously hypertensive (SHR) rats. Bioenergetics of mitochondria in astrocytes from normotensive S-D rats were modified with butyrate, but this was not the case in astrocytes derived from SHR, suggesting aberrant mitochondrial function. Transcripts related to oxidative stress, butyrate transporters, butyrate metabolism, and neuroinflammation were quantified in astrocyte cultures treated with butyrate at 0, 200, 600, and 1000 μmol/L. Butyrate decreased catalase and monocarboxylate transporter 1 mRNA in astrocytes of S-D rats but not in the SHR. Moreover, while butyrate did not directly regulate the expression of 3-hydroxybutyrate dehydrogenase 1 and 2 in astrocytes of either strain, the expression levels for these transcripts in untreated cultures were lower in the SHR compared to S-D. We observed higher levels of specific inflammatory cytokines in astrocytes of SHR, and treatment with butyrate decreased expression of Ccl2 and Tlr4 in SHR astrocytes only. Conversely, butyrate treatment increased expression of tumor necrosis factor in astrocytes from SHR but not from the S-D rats. This study improves our understanding of the role of microbial metabolites in regulating astrocyte function, and provides support that butyrate differentially regulates both the bioenergetics and transcripts related to neuroinflammation in astrocytes from SHR versus S-D rats.
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Affiliation(s)
- Tao Yang
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Vermali Rodriguez
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida
| | - Wendi L Malphurs
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Jordan T Schmidt
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Niousha Ahmari
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Colin Sumners
- Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida
| | - Christopher J Martyniuk
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Jasenka Zubcevic
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida
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Elsaafien K, Korim WS, Setiadi A, May CN, Yao ST. Chemoattraction and Recruitment of Activated Immune Cells, Central Autonomic Control, and Blood Pressure Regulation. Front Physiol 2019; 10:984. [PMID: 31427987 PMCID: PMC6688384 DOI: 10.3389/fphys.2019.00984] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 07/15/2019] [Indexed: 12/16/2022] Open
Abstract
Inflammatory mediators play a critical role in the regulation of sympathetic outflow to cardiovascular organs in hypertension. Emerging evidence highlights the involvement of immune cells in the regulation of blood pressure. However, it is still unclear how these immune cells are activated and recruited to key autonomic brain regions to regulate sympathetic outflow to cardiovascular organs. Chemokines such as C-C motif chemokine ligand 2 (CCL2), and pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), are upregulated both peripherally and centrally in hypertension. More specifically, they are upregulated in key autonomic brain regions that control sympathetic activity and blood pressure such as the paraventricular nucleus of the hypothalamus and the rostral ventrolateral medulla. Furthermore, this upregulation of inflammatory mediators is associated with the infiltration of immune cells to these brain areas. Thus, expression of pro-inflammatory chemokines and cytokines is a potential mechanism promoting invasion of immune cells into key autonomic brain regions. In pathophysiological conditions, this can result in abnormal activation of brain circuits that control sympathetic nerve activity to cardiovascular organs and ultimately in increases in blood pressure. In this review, we discuss emerging evidence that helps explain how immune cells are chemoattracted to autonomic nuclei and contribute to changes in sympathetic outflow and blood pressure.
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Affiliation(s)
- Khalid Elsaafien
- Discovery Science, Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
| | - Willian S. Korim
- Discovery Science, Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
| | - Anthony Setiadi
- Discovery Science, Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
| | - Clive N. May
- Discovery Science, Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
| | - Song T. Yao
- Discovery Science, Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
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Cardiovascular and hidroelectrolytic changes in rats fed with high-fat diet. Behav Brain Res 2019; 373:112075. [PMID: 31284013 DOI: 10.1016/j.bbr.2019.112075] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 06/14/2019] [Accepted: 07/05/2019] [Indexed: 01/18/2023]
Abstract
Obesity activates the renin-angiotensin and sympathetic systems facilitating hypertension and changes in the hydroelectrolytic balance. In the present study, in rats fed with high-fat diet (HFD), we investigated daily water intake and urinary excretion, prandial consumption of water and the changes in blood pressure and water intake to intracerebroventricular (icv) angiotensin II (ANG II). Male Holtzman rats (290-320 g) were fed with standard diet (SD, 11% calories from fat) or HFD (45% calories from fat) for 6 weeks. Part of the animals received a stainless steel cannula in the lateral ventricle (LV) at the 6th week after the beginning of the diets and the experiments were performed at the 7th week. The pressor effect, but not the dipsogenic response to acute icv injection of ANG II, was potentiated in the HFD rats. Daily water intake and urinary volume were reduced in rats fed with HFD with no significant changes in sodium excretion. Prandial water consumption was also reduced in rats ingesting HFD, an effect almost totally reverted blocking salivation with atropine. These results show a potentiation of the pressor response to icv ANG II in HFD-fed rats, without changing icv ANG II-induced water intake. In addition, prandial and daily water intake and urinary volume were reduced in HFD-fed rats, without changing sodium excretion. Salivation in rats ingesting HFD may play a role in the reduced prandial and daily water intake.
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Prehypertension exercise training attenuates hypertension and cardiac hypertrophy accompanied by temporal changes in the levels of angiotensin II and angiotensin (1-7). Hypertens Res 2019; 42:1745-1756. [DOI: 10.1038/s41440-019-0297-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 04/07/2019] [Accepted: 06/02/2019] [Indexed: 12/21/2022]
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Carnagarin R, Matthews V, Zaldivia MTK, Peter K, Schlaich MP. The bidirectional interaction between the sympathetic nervous system and immune mechanisms in the pathogenesis of hypertension. Br J Pharmacol 2019; 176:1839-1852. [PMID: 30129037 PMCID: PMC6534787 DOI: 10.1111/bph.14481] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 07/26/2018] [Accepted: 08/05/2018] [Indexed: 12/14/2022] Open
Abstract
Over the last few years, evidence has accumulated to suggest that hypertension is, at least in part, an immune-mediated inflammatory disorder. Many links between immunity and hypertension have been established and provide a complex framework of mechanistic interactions contributing to the rise in BP. These include immune-mediated inflammatory processes affecting regulatory brain nuclei and interactions with other mediators of cardiovascular regulation such as the sympathetic nervous system. Sympathoexcitation differentially regulates T-cells based upon activation status of the immune cell as well as the resident organ. Exogenous and endogenous triggers activate signalling pathways in innate and adaptive immune cells resulting in pro-inflammatory cytokine production and activation of T-lymphocytes in the cardiovascular and renal regions, now considered major factors in the development of essential hypertension. The inflammatory cascade is sustained and exacerbated by the immune flow via the brain-bone marrow-spleen-gastrointestinal axis and thereby further aggravating immune-mediated pathways resulting in a vicious cycle of established hypertension and target organ damage. This review summarizes the evidence and recent advances in linking immune-mediated inflammation, sympathetic activation and their bidirectional interactions with the development of hypertension. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.
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Affiliation(s)
- Revathy Carnagarin
- Dobney Hypertension Centre, School of Medicine – Royal Perth Hospital UnitThe University of Western AustraliaPerthWAAustralia
| | - Vance Matthews
- Dobney Hypertension Centre, School of Medicine – Royal Perth Hospital UnitThe University of Western AustraliaPerthWAAustralia
| | - Maria T K Zaldivia
- Atherothrombosis and Vascular BiologyBaker Heart and Diabetes InstituteMelbourneVicAustralia
- Department of MedicineMonash University, Royal Perth HospitalPerthWAAustralia
| | - Karlheinz Peter
- Atherothrombosis and Vascular BiologyBaker Heart and Diabetes InstituteMelbourneVicAustralia
- Department of MedicineMonash University, Royal Perth HospitalPerthWAAustralia
| | - Markus P Schlaich
- Dobney Hypertension Centre, School of Medicine – Royal Perth Hospital UnitThe University of Western AustraliaPerthWAAustralia
- Department of CardiologyRoyal Perth HospitalPerthWAAustralia
- Department of NephrologyRoyal Perth HospitalPerthWAAustralia
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Graton ME, Potje SR, Troiano JA, Vale GT, Perassa LA, Nakamune ACMS, Tirapelli CR, Bendhack LM, Antoniali C. Apocynin alters redox signaling in conductance and resistance vessels of spontaneously hypertensive rats. Free Radic Biol Med 2019; 134:53-63. [PMID: 30586635 DOI: 10.1016/j.freeradbiomed.2018.12.026] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 12/18/2018] [Accepted: 12/20/2018] [Indexed: 01/28/2023]
Abstract
Chronic treatment with apocynin reduces blood pressure and prevents endothelial dysfunction development in spontaneously hypertensive rats (SHR). Mechanisms underlying apocynin effects on SHR remain unclear. Compared to diapocynin and other drugs, apocynin is a weak antioxidant, which suggests that its effects on SHR are associated with other mechanisms besides its antioxidant capacity. Angiotensin (Ang) II regulates NOX, the major reactive oxygen species (ROS) source in the cardiovascular system. We hypothesized that, by inhibiting NOX, apocynin could alter Ang II pressor and vasoconstrictor effects on SHR. We analyzed how Ang II affects blood pressure and vascular reactivity in aorta and mesenteric resistance arteries and evaluated plasma antioxidant capacity, NOX isoforms and subunits, NOS isoforms, AT1 and AT2 receptors expression, ROS production, and NOS activity in apocynin-treated SHR blood vessels (30 mg/Kg/day, p.o.). In SHR, apocynin reduced Ang II pressor effects, increased plasmatic antioxidant capacity, and blunted aortic and mesenteric NOX-dependent oxidants production and NOX2 and p47phox overexpression, which demonstrated that apocynin inhibits NOX in SHR blood vessels. Moreover, apocynin raised plasmatic and aortic nitrate/nitrite levels, maintained NOS activity and eNOS, p-eNOS, nNOS, iNOS, sGC-α, and sGC-β expression in mesenteric bed, diminished AT1 expression in aorta and mesenteric bed, and elevated AT2 expression in SHR aorta. Apocynin increased Ang II vasoconstriction endothelial modulation in SHR resistance arteries. All these results showed that in vivo treatment with apocynin alters several mechanisms that reduce Ang II pressor and vasoconstrictor effects on SHR. Such apocynin effects involve other mechanisms besides vascular ROS modulation, which improves NO availability in SHR vascular cells. These integrated data could help us to understand the promising apocynin activity as an antihypertensive drug that acts differently from the drugs that are currently being used in the clinical setting.
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Affiliation(s)
- Murilo E Graton
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil; São Paulo State University (UNESP), School of Dentistry, Araçatuba, Department of Basic Sciences, Araçatuba, São Paulo 16015-050, Brazil
| | - Simone R Potje
- University of São Paulo (USP), Faculty of Pharmaceutical Sciences of Ribeirão Preto, Department of Physics and Chemistry, Ribeirão Preto, São Paulo 14040-903, Brazil
| | - Jéssica A Troiano
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil; São Paulo State University (UNESP), School of Dentistry, Araçatuba, Department of Basic Sciences, Araçatuba, São Paulo 16015-050, Brazil
| | - Gabriel T Vale
- University of São Paulo (USP), College of Nursing of Ribeirão Preto, Department of Psychiatry Nursing and Human Sciences, Ribeirão Preto, São Paulo 14040-902, Brazil
| | - Ligia A Perassa
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil; São Paulo State University (UNESP), School of Dentistry, Araçatuba, Department of Basic Sciences, Araçatuba, São Paulo 16015-050, Brazil
| | - Ana Cláudia M S Nakamune
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil; São Paulo State University (UNESP), School of Dentistry, Araçatuba, Department of Basic Sciences, Araçatuba, São Paulo 16015-050, Brazil
| | - Carlos R Tirapelli
- University of São Paulo (USP), College of Nursing of Ribeirão Preto, Department of Psychiatry Nursing and Human Sciences, Ribeirão Preto, São Paulo 14040-902, Brazil
| | - Lusiane M Bendhack
- University of São Paulo (USP), Faculty of Pharmaceutical Sciences of Ribeirão Preto, Department of Physics and Chemistry, Ribeirão Preto, São Paulo 14040-903, Brazil
| | - Cristina Antoniali
- Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas, SBFis, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil; São Paulo State University (UNESP), School of Dentistry, Araçatuba, Department of Basic Sciences, Araçatuba, São Paulo 16015-050, Brazil.
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Żera T, Nowiński A, Segiet A, Smykiewicz P. Microglia and brain angiotensin type 1 receptors are involved in desensitising baroreflex by intracerebroventricular hypertonic saline in male Sprague-Dawley rats. Auton Neurosci 2019; 217:49-57. [PMID: 30704975 DOI: 10.1016/j.autneu.2019.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 01/04/2019] [Accepted: 01/04/2019] [Indexed: 12/09/2022]
Abstract
High salt diet alters cardiovascular control by increasing concentration of sodium ions (Na+) in cerebrospinal fluid (CSF) and is a risk factor for hypertension. Hypernatremic conditions activate microglia and upregulate renin-angiotensin system in the brain. Thus, we checked if chronic elevation of CSF Na+ affects neural control of circulatory system via microglia and brain angiotensin type 1 receptors (AT1Rs). Normotensive adult male Sprague-Dawley rats received two-week intracerebroventricular (ICV) infusion of either isoosmotic saline (0.9% NaCl); hyperosmotic saline (5% NaCl); 5% NaCl with minocycline - inhibitor of microglia; 5% NaCl with losartan - AT1R blocker. Fluid intake, urine output, and urinary Na+ excretion were measured before and during ICV infusions. At the end of ICV infusions, blood pressure and heart rate were recorded in awake rats at rest, in response to acute air jet stressor, during pharmacological evaluation of baroreflex, and after autonomic ganglia blockade. CSF and blood were collected for evaluation of Na+ concentration. Baroreflex was blunted in rats ICV infused with 5% NaCl. ICV treatment with losartan or minocycline prevented decrease in baroreflex sensitivity. Hemodynamic parameters at rest, in response to acute stressor and autonomic ganglia blockade were similar in all groups. Neither treatment affected water intake, urine output and urinary Na+ excretion. ICV infusion of 5% NaCl resulted in higher concentration of Na+ in CSF than in control group (0.9% NaCl) and in plasma. Our results indicate that chronic ICV infusion of hyperosmotic saline blunts baroreflex in normotensive rats and this desensitization is mediated by microglia and AT1Rs.
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Affiliation(s)
- Tymoteusz Żera
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, the Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
| | - Artur Nowiński
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, the Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
| | - Agnieszka Segiet
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, the Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
| | - Paweł Smykiewicz
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, the Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
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Segiet A, Smykiewicz P, Kwiatkowski P, Żera T. Tumour necrosis factor and interleukin 10 in blood pressure regulation in spontaneously hypertensive and normotensive rats. Cytokine 2019; 113:185-194. [DOI: 10.1016/j.cyto.2018.07.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 04/30/2018] [Accepted: 07/02/2018] [Indexed: 02/07/2023]
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Abstract
The causes of essential hypertension remain an enigma. Interactions between genetic and external factors are generally recognized to act as aetiological mechanisms that trigger the pathogenesis of high blood pressure. However, the questions of which genes and factors are involved, and when and where such interactions occur, remain unresolved. Emerging evidence indicates that the hypertensive response to pressor stimuli, like many other physiological and behavioural adaptations, can become sensitized to particular stimuli. Studies in animal models show that, similarly to other response systems controlled by the brain, hypertensive response sensitization (HTRS) is mediated by neuroplasticity. The brain circuitry involved in HTRS controls the sympathetic nervous system. This Review outlines evidence supporting the phenomenon of HTRS and describes the range of physiological and psychosocial stressors that can produce a sensitized hypertensive state. Also discussed are the cellular and molecular changes in the brain neural network controlling sympathetic tone involved in long-term storage of information relating to stressors, which could serve to maintain a sensitized state. Finally, this Review concludes with a discussion of why a sensitized hypertensive response might previously have been beneficial and increased biological fitness under some environmental conditions and why today it has become a health-related liability.
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Affiliation(s)
- Alan Kim Johnson
- Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA, USA.
- Department of Health and Human Physiology, University of Iowa, Iowa City, IA, USA.
- Department of Pharmacology, University of Iowa, Iowa City, IA, USA.
- The François M. Abboud Cardiovascular Center, Iowa City, IA, USA.
| | - Baojian Xue
- Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA, USA
- The François M. Abboud Cardiovascular Center, Iowa City, IA, USA
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Blockade of Endogenous Angiotensin-(1-7) in Hypothalamic Paraventricular Nucleus Attenuates High Salt-Induced Sympathoexcitation and Hypertension. Neurosci Bull 2018; 35:47-56. [PMID: 30328008 DOI: 10.1007/s12264-018-0297-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 08/24/2018] [Indexed: 12/18/2022] Open
Abstract
Angiotensin (Ang)-(1-7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1-7) in the hypothalamic paraventricular nucleus (PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines (PICs) and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt (8% NaCl) or a normal salt diet (0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1-7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma norepinephrine (NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91phox expression and superoxide production in the PVN. Microinjection of A-779 (3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1-7) in the PVN, through modulation of PICs and oxidative stress.
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Smykiewicz P, Segiet A, Keag M, Żera T. Proinflammatory cytokines and ageing of the cardiovascular-renal system. Mech Ageing Dev 2018; 175:35-45. [DOI: 10.1016/j.mad.2018.07.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 07/01/2018] [Accepted: 07/19/2018] [Indexed: 12/11/2022]
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Simpson NJ, Ferguson AV. Tumor necrosis factor-α potentiates the effects of angiotensin II on subfornical organ neurons. Am J Physiol Regul Integr Comp Physiol 2018; 315:R425-R433. [DOI: 10.1152/ajpregu.00044.2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Inflammation is thought to play a fundamental role in the pathophysiology of hypertension and heart failure, although the mechanisms for this remain unclear. Proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), influence the subfornical organ (SFO) to modulate sympathetic activity and blood pressure. The pressor effects of TNF-α in the SFO are partially mediated by angiotensin II (ANG II) receptor type 1 (AT1R), and TNF-α is known to potentiate ANG II-induced hypertension. However, the cellular mechanism of the interaction between TNF-α and ANG II/AT1R signaling remains unknown. In the present study, we performed Ca2+ imaging on dissociated SFO neurons in vitro from male Sprague-Dawley rats to determine whether TNF-α modulates ANG II-induced increases in intracellular Ca2+ in SFO neurons. We first established that a proportion of SFO neurons respond to ANG II, an effect that required AT1R signaling and extracellular Ca2+. We then tested the hypothesis that TNF-α may modulate the effects of ANG II on SFO neurons by examining the effects of TNF-α treatment on the ANG II-induced rise in intracellular Ca2+. We discovered that TNF-α potentiated the ANG II-induced rise in intracellular Ca2+, an effect that was dependent on the duration of TNF-α treatment. Finally, we determined that this potentiation of ANG II-induced Ca2+ activity relied on tetrodotoxin-sensitive voltage-gated Na+ (vgNa+) channels. These data suggest that the potentiation of ANG II/AT1R activity by TNF-α in SFO neurons results from the previously demonstrated ability of this cytokine to modulate the activation threshold of vgNa+ currents.
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Affiliation(s)
- Nick J. Simpson
- Center for Neuroscience Studies, Queen’s University, Kingston, ON, Canada
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
| | - Alastair V. Ferguson
- Center for Neuroscience Studies, Queen’s University, Kingston, ON, Canada
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
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Oyarce MP, Iturriaga R. Contribution of Oxidative Stress and Inflammation to the Neurogenic Hypertension Induced by Intermittent Hypoxia. Front Physiol 2018; 9:893. [PMID: 30050461 PMCID: PMC6050421 DOI: 10.3389/fphys.2018.00893] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 06/21/2018] [Indexed: 12/11/2022] Open
Abstract
Chronic intermittent hypoxia (CIH), the hallmark of obstructive sleep apnea, is the main risk factor to develop systemic hypertension. Oxidative stress, inflammation, and sympathetic overflow have been proposed as possible mechanisms underlying the CIH-induced hypertension. CIH potentiates the carotid body (CB) chemosensory discharge leading to sympathetic overflow, autonomic dysfunction, and hypertension. Oxidative stress and pro-inflammatory molecules are involved in neurogenic models of hypertension, acting on brainstem and hypothalamic nuclei related to the cardiorespiratory control, such as the nucleus of the solitary tract, which is the primary site for the afferent inputs from the CB. Oxidative stress and pro-inflammatory molecules contribute to the activation of the CB chemoreflex pathway in CIH-induced hypertension. In this brief review, we will discuss new evidence for a critical role of oxidative stress and neuro-inflammation in development of the CIH-induced hypertension through activation of the CB chemoreflex pathway.
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Affiliation(s)
| | - Rodrigo Iturriaga
- Laboratorio de Neurobiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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