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Lataro RM, Brognara F, Iturriaga R, Paton JFR. Inflammation of some visceral sensory systems and autonomic dysfunction in cardiovascular disease. Auton Neurosci 2024; 251:103137. [PMID: 38104365 DOI: 10.1016/j.autneu.2023.103137] [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: 07/27/2023] [Revised: 11/15/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023]
Abstract
The sensitization and hypertonicity of visceral afferents are highly relevant to the development and progression of cardiovascular and respiratory disease states. In this review, we described the evidence that the inflammatory process regulates visceral afferent sensitivity and tonicity, affecting the control of the cardiovascular and respiratory system. Some inflammatory mediators like nitric oxide, angiotensin II, endothelin-1, and arginine vasopressin may inhibit baroreceptor afferents and contribute to the baroreflex impairment observed in cardiovascular diseases. Cytokines may act directly on peripheral afferent terminals that transmit information to the central nervous system (CNS). TLR-4 receptors, which recognize lipopolysaccharide, were identified in the nodose and petrosal ganglion and have been implicated in disrupting the blood-brain barrier, which can potentiate the inflammatory process. For example, cytokines may cross the blood-brain barrier to access the CNS. Additionally, pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α and some of their receptors have been identified in the nodose ganglion and carotid body. These pro-inflammatory cytokines also sensitize the dorsal root ganglion or are released in the nucleus of the solitary tract. In cardiovascular disease, pro-inflammatory mediators increase in the brain, heart, vessels, and plasma and may act locally or systemically to activate/sensitize afferent nervous terminals. Recent evidence demonstrated that the carotid body chemoreceptor cells might sense systemic pro-inflammatory molecules, supporting the novel proposal that the carotid body is part of the afferent pathway in the central anti-inflammatory reflexes. The exact mechanisms of how pro-inflammatory mediators affects visceral afferent signals and contribute to the pathophysiology of cardiovascular diseases awaits future research.
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Affiliation(s)
- R M Lataro
- Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil.
| | - F Brognara
- Department of Nursing, General and Specialized, Nursing School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - R Iturriaga
- Facultad de Ciencias Biológicas, Pontificia Universidad Catolica de Chile, Santiago, Chile; Centro de Investigación en Fisiología y Medicina en Altura - FIMEDALT, Universidad de Antofagasta, Antofagasta, Chile
| | - J F R Paton
- Manaaki Manawa - The Centre for Heart Research, Department of Physiology, Faculty of Medical & Health Sciences, University of Auckland, Grafton, Auckland, New Zealand
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2
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Andjelkovic AV, Situ M, Citalan-Madrid AF, Stamatovic SM, Xiang J, Keep RF. Blood-Brain Barrier Dysfunction in Normal Aging and Neurodegeneration: Mechanisms, Impact, and Treatments. Stroke 2023; 54:661-672. [PMID: 36848419 PMCID: PMC9993074 DOI: 10.1161/strokeaha.122.040578] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
Cerebral endothelial cells and their linking tight junctions form a unique, dynamic and multi-functional interface, the blood-brain barrier (BBB). The endothelium is regulated by perivascular cells and components forming the neurovascular unit. This review examines BBB and neurovascular unit changes in normal aging and in neurodegenerative disorders, particularly focusing on Alzheimer disease, cerebral amyloid angiopathy and vascular dementia. Increasing evidence indicates BBB dysfunction contributes to neurodegeneration. Mechanisms underlying BBB dysfunction are outlined (endothelium and neurovascular unit mediated) as is the BBB as a therapeutic target including increasing the uptake of systemically delivered therapeutics across the BBB, enhancing clearance of potential neurotoxic compounds via the BBB, and preventing BBB dysfunction. Finally, a need for novel biomarkers of BBB dysfunction is addressed.
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Affiliation(s)
- Anuska V. Andjelkovic
- Department of Pathology, University of Michigan Medical School, Ann Arbor MI, USA
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor MI, USA
| | - Muyu Situ
- Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor MI, USA
| | | | | | - Jianming Xiang
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor MI, USA
| | - Richard F Keep
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor MI, USA
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor MI, USA
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3
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Wang J, Chen X. Junctional Adhesion Molecules: Potential Proteins in Atherosclerosis. Front Cardiovasc Med 2022; 9:888818. [PMID: 35872908 PMCID: PMC9302484 DOI: 10.3389/fcvm.2022.888818] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
Junctional adhesion molecules (JAMs) are cell-cell adhesion molecules of the immunoglobulin superfamily and are involved in the regulation of diverse atherosclerosis-related processes such as endothelial barrier maintenance, leucocytes transendothelial migration, and angiogenesis. To combine and further broaden related results, this review concluded the recent progress in the roles of JAMs and predicted future studies of JAMs in the development of atherosclerosis.
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Affiliation(s)
- Junqi Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoping Chen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Xiaoping Chen,
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Rath D, Rapp V, Schwartz J, Winter S, Emschermann F, Arnold D, Rheinlaender J, Büttcher M, Strebl M, Braun MB, Altgelt K, Uribe ÁP, Schories C, Canjuga D, Schaeffeler E, Borst O, Schäffer TE, Langer H, Stehle T, Schwab M, Geisler T, Gawaz M, Chatterjee M. Homophilic Interaction Between Transmembrane-JAM-A and Soluble JAM-A Regulates Thrombo-Inflammation: Implications for Coronary Artery Disease. JACC Basic Transl Sci 2022; 7:445-461. [PMID: 35663628 PMCID: PMC9156439 DOI: 10.1016/j.jacbts.2022.03.003] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 03/08/2022] [Accepted: 03/08/2022] [Indexed: 11/02/2022]
Abstract
Genetic predisposition through F11R-single-nucleotide variation (SNV) influences circulatory soluble junctional adhesion molecule-A (sJAM-A) levels in coronary artery disease (CAD) patients. Homozygous carriers of the minor alleles (F11R-SNVs rs2774276, rs790056) show enhanced levels of thrombo-inflammatory sJAM-A. Both F11R-SNVs and sJAM-A are associated with worse prognosis for recurrent myocardial infarction in CAD patients. Platelet surface-associated JAM-A correlate with platelet activation markers in CAD patients. Activated platelets shed transmembrane-JAM-A, generating proinflammatory sJAM-A and JAM-A-bearing microparticles. Platelet transmembrane-JAM-A and sJAM-A as homophilic interaction partners exaggerate thrombotic and thrombo-inflammatory platelet monocyte interactions. Therapeutic strategies interfering with this homophilic interface may regulate thrombotic and thrombo-inflammatory platelet response in cardiovascular pathologies where circulatory sJAM-A levels are elevated.
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Key Words
- ACM, all-cause mortality
- ACS, acute coronary syndrome
- ADP, adenosine diphosphate
- CAD, coronary artery disease
- CCS, chronic coronary syndrome
- CE, combined endpoint
- HC, homozygous carriers
- IS, ischemic stroke
- JAM-A
- JAM-A, junctional adhesion molecule-A
- MI, myocardial infarction
- SNV
- SNV, single-nucleotide variation
- TRAP, thrombin receptor activating peptide
- coronary artery disease
- platelet
- sJAM-A, soluble junctional adhesion molecule-A
- smJAM-A, soluble murine junctional adhesion molecule-A
- thrombo-inflammation
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Affiliation(s)
- Dominik Rath
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Vera Rapp
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Jessica Schwartz
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Stefan Winter
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany
| | - Frederic Emschermann
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Daniel Arnold
- Institute of Applied Physics, University of Tübingen, Tübingen, Germany
| | | | - Manuela Büttcher
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Michael Strebl
- Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Michael B. Braun
- Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Konstanze Altgelt
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Álvaro Petersen Uribe
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Christoph Schories
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Denis Canjuga
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Elke Schaeffeler
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany
| | - Oliver Borst
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
- DFG Heisenberg Group Thrombocardiology, Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | | | - Harald Langer
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Thilo Stehle
- Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Matthias Schwab
- Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany
- Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany
- Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany
| | - Tobias Geisler
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Meinrad Gawaz
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
| | - Madhumita Chatterjee
- Department of Cardiology and Angiology, University Hospital Tübingen, Tübingen, Germany
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Effect of F11R Gene Knockdown on Malignant Biological Behaviors of Pancreatic Cancer Cells. JOURNAL OF ONCOLOGY 2022; 2022:3379027. [PMID: 35295710 PMCID: PMC8920619 DOI: 10.1155/2022/3379027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/16/2022] [Accepted: 02/02/2022] [Indexed: 11/17/2022]
Abstract
F11R receptor (F11R/junctional adhesion molecule-A/F11R-A) is preferentially concentrated at tight junctions and influences epithelial cell morphology and migration. Numerous studies have shown that the aberrant expression of F11R contributes to tumor progression including pancreatic cancer. However, the significance of F11R in various tumors is controversial, and the role of F11R in regulating the malignant behaviors of human pancreatic cancer is unknown. To investigate the role of F11R in the carcinogenesis of pancreatic cancer and the potential targets of F11R as a therapeutic target for pancreatic cancer, we knocked down F11R in the pancreatic cancer cell line PANC-1 using lentiviral approaches. We found that F11R silencing led to decreased cell proliferation, a loss of cell invasiveness, cell cycle arrest in the G1 phase, and enhanced cell apoptosis. The present results suggest that F11R may be a promising therapeutic target for pancreatic cancer.
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Sisk LJ, Patel RK, Stevens KK. A descriptive analysis of non-human leukocyte antigens present in renal transplant donor-recipient pairs. Transpl Immunol 2021; 69:101474. [PMID: 34582968 DOI: 10.1016/j.trim.2021.101474] [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: 07/31/2021] [Revised: 09/22/2021] [Accepted: 09/22/2021] [Indexed: 11/16/2022]
Abstract
INTRODUCTION End stage renal disease (ESRD) is the irreversible deterioration of renal function requiring renal replacement therapy by dialysis or transplant. Human leucocyte antigens (HLA) have been well examined however research still is required into the non-HLA antibodies. Antibody mediated rejection (AMR) can be seen in the absence of HLA antibodies on biopsies of patients who have received identical transplants; anti-endothelial cell antibodies may explain this. Investigation into endothelial cell antigens on donor and recipient endothelium may elucidate and stratify the degree of risk of any given transplant and may guide towards the best matched donor. METHODS Protein array analysis was carried out on 8 patient pairs using nitro-cellulose membranes and biotinylated detection antibodies. The fluorescence emitted was captured by X-Ray film and results were recorded with ImageJ software. A fold increase of more than 2 was considered to be positive. RESULTS 11 proteins identified had a fold increase of increase ≥2 and were present in ≥2 patient pairs which may point to potential clinical utility. Nectin2/CD112 may be measured in order analyse graft survival time in transplant recipients. Prognosticating renal failure has clinical importance and potential markers that have been identified to aid which include MEPE, CRELD2, and TIMP-4. Novel pharmacological therapies for specific biomarkers identified in this study include JAM-A, E-Selectin, CD147, Galectin-3, JAM-C, PAR-1, and TNFR2. CONCLUSION Protein analysis showed differences in expression of antigens between patients with and without Chronic Kidney Disease (CKD). This information could be used at the matching stage of renal transplantation and also in the treatment of rejection episodes. The results highlight biomarkers that potentially prognosticate and pharmacological therapies that may ameliorate kidney disease and rejection in ESRD and transplant recipients.
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Affiliation(s)
- Louis J Sisk
- University of Glasgow, United Kingdom; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom.
| | - Rajan K Patel
- University of Glasgow, United Kingdom; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom
| | - Kathryn K Stevens
- University of Glasgow, United Kingdom; British Heart Foundation Cardiovascular Research Centre, University of Glasgow, United Kingdom
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7
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Hirooka Y. Sympathetic Activation in Hypertension: Importance of the Central Nervous System. Am J Hypertens 2020; 33:914-926. [PMID: 32374869 DOI: 10.1093/ajh/hpaa074] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 04/18/2020] [Accepted: 05/01/2020] [Indexed: 12/20/2022] Open
Abstract
The sympathetic nervous system plays a critical role in the pathogenesis of hypertension. The central nervous system (CNS) organizes the sympathetic outflow and various inputs from the periphery. The brain renin-angiotensin system has been studied in various regions involved in controlling sympathetic outflow. Recent progress in cardiovascular research, particularly in vascular biology and neuroscience, as well as in traditional physiological approaches, has advanced the field of the neural control of hypertension in which the CNS plays a vital role. Cardiovascular research relating to hypertension has focused on the roles of nitric oxide, oxidative stress, inflammation, and immunity, and the network among various organs, including the heart, kidney, spleen, gut, and vasculature. The CNS mechanisms are similarly networked with these factors and are widely studied in neuroscience. In this review, I describe the development of the conceptual flow of this network in the field of hypertension on the basis of several important original research articles and discuss potential future breakthroughs leading to clinical precision medicine.
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Affiliation(s)
- Yoshitaka Hirooka
- Department of Medical Technology and Sciences, School of Health Sciences at Fukuoka, International University of Health and Welfare, Okawa City, Fukuoka, Japan
- Department of Cardiovascular Medicine, Hypertension and Heart Failure Center, Takagi Hospital, Okawa City, Fukuoka, Japan
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8
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Presa JL, Saravia F, Bagi Z, Filosa JA. Vasculo-Neuronal Coupling and Neurovascular Coupling at the Neurovascular Unit: Impact of Hypertension. Front Physiol 2020; 11:584135. [PMID: 33101063 PMCID: PMC7546852 DOI: 10.3389/fphys.2020.584135] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/04/2020] [Indexed: 12/18/2022] Open
Abstract
Components of the neurovascular unit (NVU) establish dynamic crosstalk that regulates cerebral blood flow and maintain brain homeostasis. Here, we describe accumulating evidence for cellular elements of the NVU contributing to critical physiological processes such as cerebral autoregulation, neurovascular coupling, and vasculo-neuronal coupling. We discuss how alterations in the cellular mechanisms governing NVU homeostasis can lead to pathological changes in which vascular endothelial and smooth muscle cell, pericyte and astrocyte function may play a key role. Because hypertension is a modifiable risk factor for stroke and accelerated cognitive decline in aging, we focus on hypertension-associated changes on cerebral arteriole function and structure, and the molecular mechanisms through which these may contribute to cognitive decline. We gather recent emerging evidence concerning cognitive loss in hypertension and the link with vascular dementia and Alzheimer’s disease. Collectively, we summarize how vascular dysfunction, chronic hypoperfusion, oxidative stress, and inflammatory processes can uncouple communication at the NVU impairing cerebral perfusion and contributing to neurodegeneration.
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Affiliation(s)
- Jessica L Presa
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - Flavia Saravia
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - Zsolt Bagi
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Jessica A Filosa
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, United States
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9
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Brognara F, Felippe ISA, Salgado HC, Paton JFR. Autonomic innervation of the carotid body as a determinant of its sensitivity: implications for cardiovascular physiology and pathology. Cardiovasc Res 2020; 117:1015-1032. [PMID: 32832979 DOI: 10.1093/cvr/cvaa250] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 07/01/2020] [Accepted: 08/18/2020] [Indexed: 12/14/2022] Open
Abstract
The motivation for this review comes from the emerging complexity of the autonomic innervation of the carotid body (CB) and its putative role in regulating chemoreceptor sensitivity. With the carotid bodies as a potential therapeutic target for numerous cardiorespiratory and metabolic diseases, an understanding of the neural control of its circulation is most relevant. Since nerve fibres track blood vessels and receive autonomic innervation, we initiate our review by describing the origins of arterial feed to the CB and its unique vascular architecture and blood flow. Arterial feed(s) vary amongst species and, unequivocally, the arterial blood supply is relatively high to this organ. The vasculature appears to form separate circuits inside the CB with one having arterial venous anastomoses. Both sympathetic and parasympathetic nerves are present with postganglionic neurons located within the CB or close to it in the form of paraganglia. Their role in arterial vascular resistance control is described as is how CB blood flow relates to carotid sinus afferent activity. We discuss non-vascular targets of autonomic nerves, their possible role in controlling glomus cell activity, and how certain transmitters may relate to function. We propose that the autonomic nerves sub-serving the CB provide a rapid mechanism to tune the gain of peripheral chemoreflex sensitivity based on alterations in blood flow and oxygen delivery, and might provide future therapeutic targets. However, there remain a number of unknowns regarding these mechanisms that require further research that is discussed.
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Affiliation(s)
- Fernanda Brognara
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton Auckland 1023, New Zealand.,Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Igor S A Felippe
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton Auckland 1023, New Zealand
| | - Helio C Salgado
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Julian F R Paton
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton Auckland 1023, New Zealand
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Kuznik BI, Guseva ES, Davydov SO, Smolyakov YN, Tsybikov NN. The effects of the “youth protein” GDF11 and “aging proteins” ccL11, GDF15, JAM-A on cardiohemodynamics in women with essential hypertension. ACTA ACUST UNITED AC 2020. [DOI: 10.18705/1607-419x-2019-25-5-527-539] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
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11
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Walas D, Nowicki-Osuch K, Alibhai D, von Linstow Roloff E, Coghill J, Waterfall C, Paton JF. Inflammatory pathways are central to posterior cerebrovascular artery remodelling prior to the onset of congenital hypertension. J Cereb Blood Flow Metab 2019; 39:1803-1817. [PMID: 29651914 PMCID: PMC6724458 DOI: 10.1177/0271678x18769180] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Cerebral artery hypoperfusion may provide the basis for linking ischemic stroke with hypertension. Brain hypoperfusion may induce hypertension that may serve as an auto-protective mechanism to prevent ischemic stroke. We hypothesised that hypertension is caused by remodelling of the cerebral arteries, which is triggered by inflammation. We used a congenital rat model of hypertension and examined age-related changes in gene expression of the cerebral arteries using RNA sequencing. Prior to hypertension, we found changes in signalling pathways associated with the immune system and fibrosis. Validation studies using second harmonics generation microscopy revealed upregulation of collagen type I and IV in both tunica externa and media. These changes in the extracellular matrix of cerebral arteries pre-empted hypertension accounting for their increased stiffness and resistance, both potentially conducive to stroke. These data indicate that inflammatory driven cerebral artery remodelling occurs prior to the onset of hypertension and may be a trigger elevating systemic blood pressure in genetically programmed hypertension.
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Affiliation(s)
- Dawid Walas
- 1 School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK
| | | | - Dominic Alibhai
- 3 Wolfson Bioimaging Facility, School of Biochemistry, Biomedical Sciences, University of Bristol, Bristol, UK
| | - Eva von Linstow Roloff
- 1 School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK
| | - Jane Coghill
- 4 Genomics Facility, School of Biological Sciences, Bristol, UK
| | | | - Julian Fr Paton
- 1 School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.,5 Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Grafton, New Zealand
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12
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Krochmal M, Cisek K, Filip S, Markoska K, Orange C, Zoidakis J, Gakiopoulou C, Spasovski G, Mischak H, Delles C, Vlahou A, Jankowski J. Identification of novel molecular signatures of IgA nephropathy through an integrative -omics analysis. Sci Rep 2017; 7:9091. [PMID: 28831120 PMCID: PMC5567309 DOI: 10.1038/s41598-017-09393-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 07/26/2017] [Indexed: 12/19/2022] Open
Abstract
IgA nephropathy (IgAN) is the most prevalent among primary glomerular diseases worldwide. Although our understanding of IgAN has advanced significantly, its underlying biology and potential drug targets are still unexplored. We investigated a combinatorial approach for the analysis of IgAN-relevant -omics data, aiming at identification of novel molecular signatures of the disease. Nine published urinary proteomics datasets were collected and the reported differentially expressed proteins in IgAN vs. healthy controls were integrated into known biological pathways. Proteins participating in these pathways were subjected to multi-step assessment, including investigation of IgAN transcriptomics datasets (Nephroseq database), their reported protein-protein interactions (STRING database), kidney tissue expression (Human Protein Atlas) and literature mining. Through this process, from an initial dataset of 232 proteins significantly associated with IgAN, 20 pathways were predicted, yielding 657 proteins for further analysis. Step-wise evaluation highlighted 20 proteins of possibly high relevance to IgAN and/or kidney disease. Experimental validation of 3 predicted relevant proteins, adenylyl cyclase-associated protein 1 (CAP1), SHC-transforming protein 1 (SHC1) and prolylcarboxypeptidase (PRCP) was performed by immunostaining of human kidney sections. Collectively, this study presents an integrative procedure for -omics data exploitation, giving rise to biologically relevant results.
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Affiliation(s)
- Magdalena Krochmal
- Biomedical Research Foundation Academy of Athens, Center of Basic Research, Athens, Greece
- RWTH Aachen University Hospital, Institute for Molecular Cardiovascular Research, Aachen, Germany
| | | | - Szymon Filip
- Biomedical Research Foundation Academy of Athens, Center of Basic Research, Athens, Greece
| | - Katerina Markoska
- Department of Nephrology, Medical Faculty, University of Skopje, Skopje, Macedonia
| | - Clare Orange
- Department of Pathology, School of Medicine, University of Glasgow, Glasgow, UK
| | - Jerome Zoidakis
- Biomedical Research Foundation Academy of Athens, Center of Basic Research, Athens, Greece
| | - Chara Gakiopoulou
- Pathology Department, National and Kapodistrian University of Athens, Athens, Greece
| | - Goce Spasovski
- Department of Nephrology, Medical Faculty, University of Skopje, Skopje, Macedonia
| | - Harald Mischak
- Mosaiques Diagnostics GmbH, Hannover, Germany
- University of Glasgow, Institute of Cardiovascular and Medical Sciences, Glasgow, UK
| | - Christian Delles
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK
| | - Antonia Vlahou
- Biomedical Research Foundation Academy of Athens, Center of Basic Research, Athens, Greece.
| | - Joachim Jankowski
- RWTH Aachen University Hospital, Institute for Molecular Cardiovascular Research, Aachen, Germany.
- University of Maastricht, CARIM School for Cardiovascular Diseases, Maastricht, Netherlands.
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13
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Marvar PJ, Hendy EB, Cruise TD, Walas D, DeCicco D, Vadigepalli R, Schwaber JS, Waki H, Murphy D, Paton JFR. Systemic leukotriene B 4 receptor antagonism lowers arterial blood pressure and improves autonomic function in the spontaneously hypertensive rat. J Physiol 2016; 594:5975-5989. [PMID: 27230966 DOI: 10.1113/jp272065] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 05/09/2016] [Indexed: 12/19/2022] Open
Abstract
KEY POINTS Evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B4 (LTB4 ), a potent chemoattractant involved in the inflammatory response, but its mode of action is poorly understood. In the SHR, we observed an increase in T cells and macrophages in the brainstem; in addition, gene expression profiling data showed that LTB4 production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. When LTB4 receptor 1 (BLT1) receptors were blocked with CP-105,696, arterial pressure was reduced in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in systolic blood pressure (BP) indicators. These data provide new evidence for the role of LTB4 as an important neuro-immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension. ABSTRACT Accumulating evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B4 (LTB4 ), a potent chemoattractant involved in the inflammatory response. However, the mechanism for LTB4 -mediated inflammation in hypertension is poorly understood. Here we report in the SHR, increased brainstem infiltration of T cells and macrophages plus gene expression profiling data showing that LTB4 production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. Chronic blockade of the LTB4 receptor 1 (BLT1) receptor with CP-105,696, reduced arterial pressure in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in low and high frequency spectra of systolic blood pressure, and an increase in spontaneous baroreceptor reflex gain (sBRG). These data provide new evidence for the role of LTB4 as an important neuro-immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension.
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Affiliation(s)
- Paul J Marvar
- Department of Pharmacology and Physiology Washington, The George Washington University School of Medical and Health Sciences, Washington, DC, USA
| | - Emma B Hendy
- School of Physiology, Pharmacology & Neuroscience, Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK
| | - Thomas D Cruise
- School of Physiology, Pharmacology & Neuroscience, Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK
| | - Dawid Walas
- School of Physiology, Pharmacology & Neuroscience, Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK
| | - Danielle DeCicco
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Rajanikanth Vadigepalli
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - James S Schwaber
- Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Hidefumi Waki
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
| | - David Murphy
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, University of Bristol, Whitson Street, Bristol, BS1 3NY, UK
| | - Julian F R Paton
- School of Physiology, Pharmacology & Neuroscience, Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK.
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14
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Marina N, Teschemacher AG, Kasparov S, Gourine AV. Glia, sympathetic activity and cardiovascular disease. Exp Physiol 2016; 101:565-76. [PMID: 26988631 PMCID: PMC5031202 DOI: 10.1113/ep085713] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 03/10/2016] [Indexed: 12/13/2022]
Abstract
NEW FINDINGS What is the topic of this review? In this review, we discuss recent findings that provide a novel insight into the mechanisms that link glial cell function with the pathogenesis of cardiovascular disease, including systemic arterial hypertension and chronic heart failure. What advances does it highlight? We discuss how glial cells may influence central presympathetic circuits, leading to maladaptive and detrimental increases in sympathetic activity and contributing to the development and progression of cardiovascular disease. Increased activity of the sympathetic nervous system is associated with the development of cardiovascular disease and may contribute to its progression. Vasomotor and cardiac sympathetic activities are generated by the neuronal circuits located in the hypothalamus and the brainstem. These neuronal networks receive multiple inputs from the periphery and other parts of the CNS and, at a local level, may be influenced by their non-neuronal neighbours, in particular glial cells. In this review, we discuss recent experimental evidence suggesting that astrocytes and microglial cells are able to modulate the activity of sympathoexcitatory neural networks in disparate physiological and pathophysiological conditions. We focus on the chemosensory properties of astrocytes residing in the rostral ventrolateral medulla oblongata and discuss signalling mechanisms leading to glial activation during brain hypoxia and inflammation. Alterations in these mechanisms may lead to heightened activity of sympathoexcitatory CNS circuits and contribute to maladaptive and detrimental increases in sympathetic tone associated with systemic arterial hypertension and chronic heart failure.
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Affiliation(s)
- Nephtali Marina
- Department of Clinical Pharmacology, University College London, London, WC1E 6JF, UK
| | - Anja G Teschemacher
- School of Physiology and Pharmacology, Medical Sciences Building, Bristol Heart Institute, University of Bristol, Bristol, BS8 1TD, UK
| | - Sergey Kasparov
- School of Physiology and Pharmacology, Medical Sciences Building, Bristol Heart Institute, University of Bristol, Bristol, BS8 1TD, UK
| | - Alexander V Gourine
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology & Pharmacology, University College London, London, WC1E 6BT, UK
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15
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Kourtesis I, Kasparov S, Verkade P, Teschemacher AG. Ultrastructural Correlates of Enhanced Norepinephrine and Neuropeptide Y Cotransmission in the Spontaneously Hypertensive Rat Brain. ASN Neuro 2015; 7:7/5/1759091415610115. [PMID: 26514659 PMCID: PMC4641560 DOI: 10.1177/1759091415610115] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The spontaneously hypertensive rat (SHR) replicates many clinically relevant features of human essential hypertension and also exhibits behavioral symptoms of attention-deficit/hyperactivity disorder and dementia. The SHR phenotype is highly complex and cannot be explained by a single genetic or physiological mechanism. Nevertheless, numerous studies including our own work have revealed striking differences in central catecholaminergic transmission in SHR such as increased vesicular catecholamine content in the ventral brainstem. Here, we used immunolabeling followed by confocal microscopy and electron microscopy to quantify vesicle sizes and populations across three catecholaminergic brain areas—nucleus tractus solitarius and rostral ventrolateral medulla, both key regions for cardiovascular control, and the locus coeruleus. We also studied colocalization of neuropeptide Y (NPY) in norepinephrine and epinephrine-containing neurons as NPY is a common cotransmitter with central and peripheral catecholamines. We found significantly increased expression and coexpression of NPY in norepinephrine and epinephrine-positive neurons of locus coeruleus in SHR compared with Wistar rats. Ultrastructural analysis revealed immunolabeled vesicles of 150 to 650 nm in diameter (means ranging from 250 to 300 nm), which is much larger than previously reported. In locus coeruleus and rostral ventrolateral medulla, but not in nucleus tractus solitarius, of SHR, noradrenergic and adrenergic vesicles were significantly larger and showed increased NPY colocalization when compared with Wistar rats. Our morphological evidence underpins the hypothesis of hyperactivity of the noradrenergic and adrenergic system and increased norepinephrine and epinephrine and NPY cotransmission in specific brain areas in SHR. It further strengthens the argument for a prohypertensive role of C1 neurons in the rostral ventrolateral medulla as a potential causative factor for essential hypertension.
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Affiliation(s)
- Ioannis Kourtesis
- School of Physiology & Pharmacology, University of Bristol, UK Bristol Heart Institute, University of Bristol, UK Sars International Centre for Marine Molecular Biology, University of Bergen, Norway
| | - Sergey Kasparov
- School of Physiology & Pharmacology, University of Bristol, UK Bristol Heart Institute, University of Bristol, UK
| | - Paul Verkade
- School of Physiology & Pharmacology, University of Bristol, UK Bristol Heart Institute, University of Bristol, UK School of Biochemistry, University of Bristol, UK Wolfson Bioimaging Facility, University of Bristol, UK
| | - Anja G Teschemacher
- School of Physiology & Pharmacology, University of Bristol, UK Bristol Heart Institute, University of Bristol, UK
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16
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Rabbit sera containing compound danshen dripping pill attenuate leukocytes adhesion to TNF-alpha--activated human umbilical vein endothelial cells by suppressing endothelial ICAM-1 and VCAM-1 expression through NF-kappaB signaling pathway. J Cardiovasc Pharmacol 2014; 63:323-32. [PMID: 24710469 DOI: 10.1097/fjc.0000000000000046] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The adherence to circulating leukocytes, such as monocytes and neutrophils, to vascular endothelial cells is of central importance to the pathogenesis of various cardiovascular diseases (CVDs) including atherosclerosis and myocardial ischemia-reperfusion injury. Compound danshen dripping pill (CDDP; Fufang Danshen Diwan in Chinese), namely cardiotonic pill, is extensively used for CVDs medication in China and some other countries. Here, we sought to investigate the effect of CDDP on leukocytes binding to vascular endothelial cells and elaborate the possibly underlying mechanism. Using seropharmacological method, rabbit sera containing CDDP were shown to mitigate the adhesiveness of monocytes and neutrophils to tumor necrosis factor alpha-stimulated human umbilical vein endothelial cells in dose and time-dependent manners, alleviate the levels of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 messenger RNA and protein dose dependently and also encumber IκBα degradation, p65 nuclear translocation, nuclear factor-kappaB (NF-κB) DNA-binding activity, and NF-κB-responsive gene transcription in tumor necrosis factor alpha-activated human umbilical vein endothelial cells. This study suggests that CDDP protects against CVDs potentially by attenuation of leukocytes-endothelium adhesion cascade via lessening endothelial cell adhesion molecules expression and NF-κB signaling pathway activity.
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17
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Williams DW, Anastos K, Morgello S, Berman JW. JAM-A and ALCAM are therapeutic targets to inhibit diapedesis across the BBB of CD14+CD16+ monocytes in HIV-infected individuals. J Leukoc Biol 2014; 97:401-12. [PMID: 25420915 DOI: 10.1189/jlb.5a0714-347r] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Monocyte transmigration across the BBB is a critical step in the development of cognitive deficits termed HAND that affect 40-70% of HIV-infected individuals, even with successful antiretroviral therapy. The monocyte subsets that enter the CNS during HIV infection are not fully characterized. We examined PBMC from HIV-positive individuals from 2 distinct cohorts and enumerated monocyte populations, characterized their transmigration properties across an in vitro human BBB model, and identified surface proteins critical for the entry of these cells into the CNS. We demonstrated that the frequency of peripheral blood CD14(+)CD16(+) and CD14(low)CD16(+) monocytes was increased in HIV-seropositive compared with -seronegative individuals, despite virologic control. We showed that CD14(+)CD16(+) monocytes selectively transmigrated across our BBB model as a result of their increased JAM-A and ALCAM expression. Antibody blocking of these proteins inhibited diapedesis of CD14(+)CD16(+) monocytes but not of T cells from the same HIV-infected people across the BBB. Our data indicate that JAM-A and ALCAM are therapeutic targets to decrease the entry of CD14(+)CD16(+) monocytes into the CNS of HIV-seropositive individuals, contributing to the eradication of neuroinflammation, HAND, and CNS viral reservoirs.
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Affiliation(s)
- Dionna W Williams
- Departments of *Pathology, Medicine and Epidemiology and Population Health, and Microbiology and Immunology, The Albert Einstein College of Medicine, Bronx, New York, USA; and Departments of Neurology, Neuroscience, and Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Kathryn Anastos
- Departments of *Pathology, Medicine and Epidemiology and Population Health, and Microbiology and Immunology, The Albert Einstein College of Medicine, Bronx, New York, USA; and Departments of Neurology, Neuroscience, and Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Susan Morgello
- Departments of *Pathology, Medicine and Epidemiology and Population Health, and Microbiology and Immunology, The Albert Einstein College of Medicine, Bronx, New York, USA; and Departments of Neurology, Neuroscience, and Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Joan W Berman
- Departments of *Pathology, Medicine and Epidemiology and Population Health, and Microbiology and Immunology, The Albert Einstein College of Medicine, Bronx, New York, USA; and Departments of Neurology, Neuroscience, and Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
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18
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Atherogenic mononuclear cell recruitment is facilitated by oxidized lipoprotein-induced endothelial junctional adhesion molecule-A redistribution. Atherosclerosis 2014; 234:254-64. [PMID: 24704627 DOI: 10.1016/j.atherosclerosis.2014.03.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 02/28/2014] [Accepted: 03/13/2014] [Indexed: 02/02/2023]
Abstract
BACKGROUND Junctional adhesion molecule (JAM-) A is a transmembrane protein expressed in many cell types and maintains junctional integrity in endothelial cells. Upon inflammatory stimulation, JAM-A relocates to the apical surface and might thereby facilitate the recruitment of leukocytes. OBJECTIVE Although inflammatory JAM-A redistribution is an established process, further effort is required to understand its exact role in the transmigration of mononuclear cells, particularly under atherogenic conditions. METHODS By the use of RNA interference and genetic deletion, the role of JAM-A in the transmigration of T cells and monocytes through aortic endothelial cells was investigated. JAM-A-localization and subsequent mononuclear cell rolling, adhesion and transmigration were explored during endothelial inflammation, induced by oxidized LDL or cytokines. RESULTS RNA interference or genetic deletion of JAM-A in aortic endothelial cells resulted in a decreased transmigration of mononuclear cells. Treatment of the endothelial cells with oxLDL resulted in an increase of both permeability and apical JAM-A presentation, as shown by bead adhesion and confocal microscopy experiments. Redistribution of JAM-A resulted in an increased leukocyte adhesion and transmigration, which could be inhibited with antibodies against JAM-A or by lovastatin-treatment, but not with the peroxisome proliferator activated receptor gamma-agonist pioglitazone. CONCLUSIONS This study demonstrates that redistribution of JAM-A in endothelial cells after stimulation with pro-atherogenic oxidized lipoproteins results in increased transmigration of mononuclear cells. This inflammatory dispersal of JAM-A could be counteracted with statins, revealing a novel aspect of their mechanism of action.
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19
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Waki H, Gouraud SS. Brain inflammation in neurogenic hypertension. World J Hypertens 2014; 4:1-6. [DOI: 10.5494/wjh.v4.i1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 11/14/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
One likely mechanism of essential hypertension (EH) is increased sympathoexcitation due to abnormal functions in the cardiovascular center of the brain. Recent findings obtained using experimental animal models of EH have shown that abnormal inflammation in the cardiovascular center may contribute to the onset of hypertension. Inflammatory molecules such as cytokines and reactive oxygen species released from the inflamed vasculature and glial cells in the medulla oblongata and hypothalamus might directly or indirectly affect neuronal functions. This in turn could increase sympathetic nerve activity and consequently arterial pressure. Abnormal inflammatory responses in the brain could also be central mechanisms underlying angiotensin II-related EH. In this review, we present the current understanding of EH mechanisms with regard to inflammatory responses in the cardiovascular center.
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20
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Wang JZ, Li SR, Li YL, Zhang YZ, Zhang T, Zhao CX, Yao CX, Du LF. Could Pin1 help us conquer essential hypertension at an earlier stage? A promising early-diagnostic biomarker and its therapeutic implications for the disease. Med Hypotheses 2013; 81:931-5. [DOI: 10.1016/j.mehy.2013.08.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Revised: 08/07/2013] [Accepted: 08/22/2013] [Indexed: 10/26/2022]
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21
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Dias da Silva VJ, Paton JFR. Introduction: the interplay between the autonomic and immune systems. Exp Physiol 2013; 97:1143-5. [PMID: 23114051 DOI: 10.1113/expphysiol.2011.061473] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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22
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McBryde FD, Abdala AP, Hendy EB, Pijacka W, Marvar P, Moraes DJA, Sobotka PA, Paton JFR. The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension. Nat Commun 2013; 4:2395. [PMID: 24002774 DOI: 10.1038/ncomms3395] [Citation(s) in RCA: 194] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 08/02/2013] [Indexed: 01/19/2023] Open
Abstract
In the spontaneously hypertensive (SH) rat, hyperoxic inactivation of the carotid body (CB) produces a rapid and pronounced fall in both arterial pressure and renal sympathetic nerve activity (RSA). Here we show that CB de-afferentation through carotid sinus nerve denervation (CSD) reduces the overactive sympathetic activity in SH rats, providing an effective antihypertensive treatment. We demonstrate that CSD lowers RSA chronically and that this is accompanied by a depressor response in SH but not normotensive rats. The drop in blood pressure is not dependent on renal nerve integrity but mechanistically accompanied by a resetting of the RSA-baroreflex function curve, sensitization of the cardiac baroreflex, changes in renal excretory function and reduced T-lymphocyte infiltration. We further show that combined with renal denervation, CSD remains effective, producing a summative response indicative of an independent mechanism. Our findings indicate that CB de-afferentation is an effective means for robust and sustained sympathoinhibition, which could translate to patients with neurogenic hypertension.
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Affiliation(s)
- Fiona D McBryde
- School of Physiology and Pharmacology, Bristol Heart Institute, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, England
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