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1.
Physiol Genomics ; 55(5): 222-234, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36939204

RESUMO

We examined the effect of chronic restraint stress and the counteractive effects of daily exercise on the molecular basis of the brain-bone marrow (BM) interactions, by especially focusing on the paraventricular nucleus (PVN) of the hypothalamus. Male Wistar rats were assigned into control, restraint stress, and stress + daily spontaneous exercise (SE) groups. BM and hypothalamic gene expression profiles were examined through the undertaking of RT-PCR and microarrays, respectively. The inflammatory blood cell population was investigated through flow cytometry. Through the use of immunohistochemistry, we examined the presence of BM-derived C-C chemokine receptor type 2 (CCR2)-expressing microglial cells in the rat PVN. The gene expression levels of BM inflammatory factors such as those of interleukin 1 beta and CCR2, and the inflammatory blood cell population were found to be significantly higher in both restrained groups compared with control group. Interestingly, chronic restraint stress alone activated the recruitment of BM-derived CCR2-expressing microglial cells into the PVN, whereas daily spontaneous exercise prevented it. A notable finding was that restraint stress upregulated relative gene expression of hypothalamic matrix metalloproteinase 3 (MMP3), which increases the permeability of the blood-brain barrier (BBB), and that exercise managed to normalize it. Moreover, relative expression of some hypothalamic genes directly involved in the facilitation of cell migration was downregulated by daily exercise. Our findings suggest that daily spontaneous exercise can reduce the numbers of BM-derived CCR2-expressing microglial cells into the PVN through the prevention of stress-induced changes in the hypothalamic gene expression.NEW & NOTEWORTHY Chronic restraint stress can upregulate MMP3 gene expression in the rat hypothalamus, whereas daily spontaneous exercise can prevent this stress-induced effect. Stress-induced BM-derived inflammatory cell recruitment into the rat PVN can be prevented by daily spontaneous exercise. Stress-induced increase of hypothalamic MMP3 gene expression may be responsible for BBB injury, thereby allowing for BM-derived inflammatory cells to be recruited and to accumulate in the rat PVN, and to be subsequently involved in the onset of stress-induced hypertension.


Assuntos
Hipertensão , Metaloproteinase 3 da Matriz , Ratos , Masculino , Animais , Ratos Wistar , Medula Óssea , Encéfalo
2.
Physiol Genomics ; 54(3): 99-114, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35100063

RESUMO

Estrogen plays a role in cardiovascular functions, emotional health, and energy homeostasis via estrogen receptors expressed in the brain. The comorbid relationship between rising blood pressure, a decline in mood and motivation, and body weight gain after menopause, when estrogen levels drop, suggests that the same brain area(s) contributes to protection from all of these postmenopausal disorders. The amygdala, a major limbic system nuclear complex known to express high estrogen receptor levels, is involved in the regulation of such physiological and psychological responses. We hypothesized that elevated estrogen levels contribute to premenopausal characteristics by activating specific genes and pathways in the amygdala. We examined the effect of 1 mo of estradiol treatment on the gene expression profile in the amygdala of ovariectomized young adult female spontaneously hypertensive rats. Estradiol substitution significantly decreased blood pressure, prevented body weight gain, and enhanced the voluntary physical activity of ovariectomized rats. In the amygdala of ovariectomized rats, estradiol treatment downregulated the expression of genes associated with estrogen signaling, cholinergic synapse, dopaminergic synapse, and long-term depression pathways. These findings indicate that the transcriptomic characteristics of the amygdala may be involved in estrogen-dependent regulation of blood pressure, physical activity motivation, and body weight control in young adult female spontaneously hypertensive rats.


Assuntos
Estradiol , Transcriptoma , Tonsila do Cerebelo/metabolismo , Animais , Peso Corporal , Estradiol/farmacologia , Estrogênios/metabolismo , Feminino , Humanos , Ovariectomia , Ratos , Ratos Endogâmicos SHR , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Transcriptoma/genética
3.
J Physiol Sci ; 68(3): 233-242, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28111704

RESUMO

Although the amygdala is known as a negative emotion center for coordinating defensive behaviors, its functions in autonomic control remain unclear. To resolve this issue, we examined effects on cardiovascular responses induced by stimulation and lesions of the amygdala in anesthetized and free-moving rats. Electrical microstimulation of the central nucleus of the amygdala (CeA) induced a gradual increase in arterial pressure (AP) and heart rate (HR), whereas stimulation of adjacent nuclei evoked a phasic AP decrease. The gain of the baroreceptor reflex was not altered by CeA stimulation, suggesting that CeA activity increases both AP and HR by resetting baroreceptor reflex function. Disinhibition of GABAergic input by amygdalar microinjection of the GABAA receptor antagonist induced robust increases in AP and HR. Furthermore, bilateral electrolytic lesions of CeA evoked consistent AP increases over the light/dark cycle. These results suggest that the amygdala exerts 'bidirectional' autonomic control over the cardiovascular system.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Estimulação Elétrica/métodos , Antagonistas de Receptores de GABA-A/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Pressorreceptores/metabolismo , Ratos , Ratos Wistar , Reflexo/efeitos dos fármacos , Reflexo/fisiologia
4.
Chronobiol Int ; 35(4): 499-510, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29271671

RESUMO

The daily rhythm of glucose metabolism is governed by the circadian clock, which consists of cell-autonomous clock machineries residing in nearly every tissue in the body. Disruption of these clock machineries either environmentally or genetically induces the dysregulation of glucose metabolism. Although the roles of clock machineries in the regulation of glucose metabolism have been uncovered in major metabolic tissues, such as the pancreas, liver, and skeletal muscle, it remains unknown whether clock function in non-major metabolic tissues also affects systemic glucose metabolism. Here, we tested the hypothesis that disruption of the clock machinery in the heart might also affect systemic glucose metabolism, because heart function is known to be associated with glucose tolerance. We examined glucose and insulin tolerance as well as heart phenotypes in mice with heart-specific deletion of Bmal1, a core clock gene. Bmal1 deletion in the heart not only decreased heart function but also led to systemic insulin resistance. Moreover, hyperglycemia was induced with age. Furthermore, heart-specific Bmal1-deficient mice exhibited decreased insulin-induced phosphorylation of Akt in the liver, thus indicating that Bmal1 deletion in the heart causes hepatic insulin resistance. Our findings revealed an unexpected effect of the function of clock machinery in a non-major metabolic tissue, the heart, on systemic glucose metabolism in mammals.


Assuntos
Fatores de Transcrição ARNTL/deficiência , Glicemia/metabolismo , Ritmo Circadiano , Resistência à Insulina , Miocárdio/metabolismo , Fatores de Transcrição ARNTL/genética , Animais , Comportamento Animal , Células Cultivadas , Ritmo Circadiano/genética , Genótipo , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Hiperglicemia/sangue , Hiperglicemia/genética , Resistência à Insulina/genética , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Tempo
5.
Glycobiology ; 28(1): 21-31, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29069492

RESUMO

Zymogen granule protein 16 (ZG16p) is a soluble lectin that binds to both mannose and heparin/heparan sulfate. It is highly expressed in the human digestive tract and is secreted into the mucus. In this study, we investigated the effect of ZG16p on the proliferation of human colorectal cancer cells. Overexpression of ZG16p in Caco-2 cells decreased cell growth. Recombinant ZG16p markedly inhibited proliferation of Caco-2, LS174T, HCT116 and HCT15 cells. Caco-2 cell growth was not inhibited by two mutated ZG16p proteins, D151A and M5 (K36A, R37A, R53A, R55A and R79A) lacking mannose- and heparin-binding activities, respectively. Immunofluorescent cell staining revealed that ZG16p-D151A maintained its binding to the Caco-2 cell surface, whereas ZG16p-M5 failed to bind to the cells. These results suggest that ZG16p interacts with the cell surface via basic amino acids substituted in ZG16p-M5 and inhibits Caco-2 cell proliferation via Asp151. In addition, growth of patient-derived colorectal tumor organoids in a 3D intestinal stem cell system was suppressed by ZG16p but not by ZG16p-M5. Taken together, our findings indicate that ZG16p inhibits the growth of colorectal cancer cells via its carbohydrate-binding sites in vitro and ex vivo. In this study, a novel pathway in cancer cell growth regulation through cell surface carbohydrate chains is suggested.


Assuntos
Carboidratos/química , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Lectinas/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Humanos , Lectinas/química , Células Tumorais Cultivadas
6.
PLoS One ; 12(12): e0189346, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29216295

RESUMO

BACKGROUND AND AIMS: We developed a bio-artificial liver (BAL) using a radial-flow bioreactor and rescued mini-pig models with lethal acute liver failure (ALF). The point of the rescue is the recovery from hepatic encephalopathy (HE). HE on ALF has sometimes resulted in brain death following brain edema with astrocyte swelling. Several factors, including ammonia and glutamine, have been reported to induce astrocyte swelling and injury. However, many clinicians believe that there are any other factors involved in the development of HE. Therefore, the aim of this study was to identify novel HE-inducible factors, particularly those inducing astrocyte dysfunction. METHODS: Mini-pig plasma samples were collected at three time points: before the administration of toxins (α-amanitin and LPS), when HE occurred after the administration of toxins, and after treatment with extracorporeal circulation (EC) by the BAL. To identify the causative factors of HE, each plasma sample was subjected to a comparative proteome analysis with two-dimensional gel electrophoresis and mass spectrometry. To assess the direct effects of candidate factors on the astrocyte function and injury, in vitro experiments with human astrocytes were performed. RESULTS: Using a proteome analysis, we identified alpha-1 antichymotrypsin (ACT), which was increased in plasma samples from mini-pigs with HE and decreased in those after treatment with EC by BAL. In in vitro experiments with human astrocytes, ACT showed growth-inhibitory and cytotoxic effects on astrocytes. In addition, the expression of water channel protein aquaporin-4, which is induced in injured astrocytes, was increased following ACT treatment. Interestingly, these effects of ACT were additively enhanced by adding arginine-vasopressin (AVP) and were canceled by adding an AVP receptor antagonist. CONCLUSIONS: These results suggest that ACT is involved in astrocyte injury and dysfunction in concert with AVP during the development of acute HE.


Assuntos
Arginina Vasopressina/metabolismo , Astrócitos/metabolismo , Encefalopatia Hepática/metabolismo , alfa 1-Antiquimotripsina/farmacologia , Doença Aguda , Cloreto de Amônio/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Linhagem Celular , Encefalopatia Hepática/patologia , Humanos , Fígado Artificial , Masculino , Suínos , Porco Miniatura
7.
Physiol Rep ; 5(5)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28292881

RESUMO

The tuberomammillary nucleus (TMN) of the posterior hypothalamus has a high density of histaminergic neurons, the projection fibers of which are present in many areas of the brain, including the nucleus tractus solitarius (NTS), which controls arterial pressure (AP). In this study, we investigated whether the TMN-NTS pathway is involved in central cardiovascular regulation. Bicuculline, a gamma-aminobutyric acid type A (GABAA) receptor antagonist, was microinjected into the ventral TMN of anesthetized rats and its effects on AP and heart rate (HR) were observed. We also evaluated the effect of cetirizine, an H1 receptor antagonist, microinjected into the NTS on cardiovascular responses induced by electrical stimulation of the TMN Both AP and HR increased following bicuculline microinjection into the ventral TMN Similar pressor and tachycardic responses were observed after electrical stimulation of the ventral TMN Microinjection of cetirizine into the NTS partially inhibited the pressor response but had no effect on HR Finally, the treadmill test was associated with a high level of c-Fos expression in both ventral TMN and NTS neurons. These results suggest that the TMN-NTS pathway is involved in regulation of AP, presumably under a high-arousal phase, such as that during exercise.


Assuntos
Pressão Arterial/efeitos dos fármacos , Cetirizina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacos , Animais , Bicuculina/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Masculino , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar
8.
PLoS One ; 9(11): e112811, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25389966

RESUMO

Cardiac function is highly dependent on oxidative energy, which is produced by mitochondrial respiration. Defects in mitochondrial function are associated with both structural and functional abnormalities in the heart. Here, we show that heart-specific ablation of the circadian clock gene Bmal1 results in cardiac mitochondrial defects that include morphological changes and functional abnormalities, such as reduced enzymatic activities within the respiratory complex. Mice without cardiac Bmal1 function show a significant decrease in the expression of genes associated with the fatty acid oxidative pathway, the tricarboxylic acid cycle, and the mitochondrial respiratory chain in the heart and develop severe progressive heart failure with age. Importantly, similar changes in gene expression related to mitochondrial oxidative metabolism are also observed in C57BL/6J mice subjected to chronic reversal of the light-dark cycle; thus, they show disrupted circadian rhythmicity. These findings indicate that the circadian clock system plays an important role in regulating mitochondrial metabolism and thereby maintains cardiac function.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Mitocôndrias/metabolismo , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Fatores de Transcrição ARNTL/metabolismo , Acetil-CoA C-Aciltransferase/metabolismo , Animais , Proteínas CLOCK/metabolismo , Isomerases de Ligação Dupla Carbono-Carbono/metabolismo , Ciclo do Ácido Cítrico/fisiologia , Transporte de Elétrons/fisiologia , Enoil-CoA Hidratase/metabolismo , Expressão Gênica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fotoperíodo , Racemases e Epimerases/metabolismo
9.
Physiol Genomics ; 45(1): 58-67, 2013 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-23132760

RESUMO

The nucleus tractus solitarii (NTS) controls the cardiovascular system during exercise, and alteration of its function may underlie exercise-induced cardiovascular adaptation. To understand the molecular basis of the NTS's plasticity in regulating blood pressure (BP) and its potential contribution to the antihypertensive effects, we characterized the gene expression profiles at the level of the NTS after long-term daily wheel running in spontaneously hypertensive rats (SHRs). Genome-wide microarray analysis was performed to screen for differentially expressed genes in the NTS between exercise-trained (12 wk) and control SHRs. Pathway analysis using the Kyoto Encyclopedia of Genes and Genomes database revealed that daily exercise altered the expression levels of NTS genes that are functionally associated with metabolic pathways (5 genes), neuroactive ligand-receptor interactions (4 genes), cell adhesion molecules (3 genes), and cytokine-cytokine receptor interactions (3 genes). One of the genes that belonged to the neuroactive ligand-receptor interactions category was histamine receptor H(1). Since we confirmed that the pressor response induced by activation of this receptor is increased after long-term daily exercise, it is suggested that functional plasticity in the histaminergic system may mediate the facilitation of blood pressure control in response to exercise but may not be involved in the lowered basal BP level found in exercise-trained SHRs. Since abnormal inflammatory states in the NTS are known to be prohypertensive in SHRs, altered gene expression of the inflammatory molecules identified in this study may be related to the antihypertensive effects in exercise-trained SHRs, although such speculation awaits functional validation.


Assuntos
Pressão Sanguínea/fisiologia , Esforço Físico/fisiologia , Ratos Endogâmicos SHR/metabolismo , Núcleo Solitário/fisiologia , Transcriptoma/genética , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Citocinas/metabolismo , Perfilação da Expressão Gênica , Imuno-Histoquímica , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Análise em Microsséries , Condicionamento Físico Animal/fisiologia , Ratos , Ratos Endogâmicos SHR/fisiologia , Receptores Histamínicos/metabolismo , Núcleo Solitário/metabolismo
10.
Endocr J ; 59(6): 447-56, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22361995

RESUMO

Understanding how the 24-hour blood-pressure rhythm is programmed has been one of the most challenging questions in cardiovascular research. The 24-hour blood-pressure rhythm is primarily driven by the circadian clock system, in which the master circadian pacemaker within the suprachiasmatic nuclei of the hypothalamus is first entrained to the light/dark cycle and then transmits synchronizing signals to the peripheral clocks common to most tissues, including the heart and blood vessels. However, the circadian system is more complex than this basic hierarchical structure, as indicated by the discovery that peripheral clocks are either influenced to some degree or fully driven by temporal changes in energy homeostasis, independent of the light entrainment pathway. Through various comparative genomic approaches and through studies exploiting mouse genetics and transgenics, we now appreciate that cardiovascular tissues possess a large number of metabolic genes whose expression cycle and reciprocally affect the transcriptional control of major circadian clock genes. These findings indicate that metabolic cycles can directly or indirectly affect the diurnal rhythm of cardiovascular function. Here, we discuss a framework for understanding how the 24-hour blood-pressure rhythm is driven by the circadian system that integrates cardiovascular and metabolic function.


Assuntos
Pressão Sanguínea/fisiologia , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Animais , Pressão Sanguínea/genética , Encéfalo/fisiologia , Proteínas CLOCK/genética , Proteínas CLOCK/fisiologia , Fenômenos Fisiológicos Cardiovasculares/genética , Sistema Cardiovascular/metabolismo , Relógios Circadianos/genética , Ritmo Circadiano/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Fotoperíodo
11.
J Hypertens ; 29(8): 1536-45, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21666494

RESUMO

OBJECTIVES: The brainstem nucleus of the solitary tract (nucleus tractus solitarii, NTS) is a pivotal region for regulating the set-point of arterial pressure, the mechanisms of which are not fully understood. Based on evidence that the NTS exhibits O2-sensing mechanisms, we examined whether a localized disturbance of blood supply, resulting in hypoxia in the NTS, would lead to an acute increase in arterial pressure. METHODS: Male Wistar rats were used. Cardiovascular parameters were measured before and after specific branches of superficial dorsal medullary veins were occluded; we assumed these were drainage vessels from the NTS and would produce stagnant hypoxia. Hypoxyprobe-1, a marker for detecting cellular hypoxia in the post-mortem tissue, was used to reveal whether vessel occlusion induced hypoxia within the NTS. RESULTS: Following vessel occlusion, blood flow in the dorsal surface of the medulla oblongata including the NTS region showed an approximately 60% decrease and was associated with hypoxia in neurons located predominantly in the caudal part of the NTS as revealed using hypoxyprobe-1. Arterial pressure increased and this response was pronounced significantly in both magnitude and duration when baroreceptor reflex afferents were sectioned. CONCLUSION: These results suggest that localized hypoxia in the NTS increases arterial pressure. We suggest this represents a protective mechanism whereby the elevated systemic pressure is a compensatory mechanism to enhance cerebral perfusion. Whether this physiological mechanism has any relevance to neurogenic hypertension is discussed.


Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/fisiopatologia , Hipóxia/fisiopatologia , Bulbo/irrigação sanguínea , Fluxo Sanguíneo Regional/fisiologia , Núcleo Solitário/irrigação sanguínea , Animais , Barorreflexo/fisiologia , Veias Cerebrais/fisiopatologia , Modelos Animais de Doenças , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Bulbo/fisiopatologia , Ratos , Ratos Wistar , Núcleo Solitário/metabolismo , Núcleo Solitário/fisiopatologia
12.
Am J Physiol Heart Circ Physiol ; 301(2): H523-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21622829

RESUMO

Axons of histamine (HA)-containing neurons are known to project from the posterior hypothalamus to many areas of the brain, including the nucleus tractus solitarii (NTS), a central brain structure that plays an important role in regulating arterial pressure. However, the functional significance of NTS HA is still not fully established. In this study, we microinjected HA or 2-pyridylethylamine, a HA-receptor H(1)-specific agonist, into the NTS of urethane-anesthetized Wister rats to identify the potential functions of NTS HA on cardiovascular regulation. When HA or H(1)-receptor-specific agonist was bilaterally microinjected into the NTS, mean arterial pressure (MAP) and heart rate (HR) were significantly increased, whereas pretreatment with the H(1)-receptor-specific antagonist cetirizine into the NTS significantly inhibited the cardiovascular responses. The maximal responses of MAP and HR changes induced by HA or H(1)-receptor-specific agonist were dose dependent. We also confirmed gene expression of HA receptors in the NTS and that the expression level of H(1) mRNA was higher than that of the other subtypes. In addition, we found that H(1) receptors are mainly expressed in neurons of the NTS. These findings suggested that HA within the NTS may play a role in regulating cardiovascular homeostasis via activation of H(1) receptors expressed in the NTS neurons.


Assuntos
Pressão Sanguínea , Frequência Cardíaca , Histamina/metabolismo , Receptores Histamínicos H1/metabolismo , Núcleo Solitário/metabolismo , Análise de Variância , Animais , Pressão Sanguínea/efeitos dos fármacos , Cetirizina/administração & dosagem , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Frequência Cardíaca/efeitos dos fármacos , Histamina/administração & dosagem , Agonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Imuno-Histoquímica , Masculino , Microinjeções , Piridinas/administração & dosagem , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H1/genética , Núcleo Solitário/efeitos dos fármacos
13.
Respir Physiol Neurobiol ; 178(3): 422-8, 2011 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-21601658

RESUMO

Essential hypertension is idiopathic although it is accepted as a complex polygenic trait with underlying genetic components, which remain unknown. Our supposition is that primary hypertension involves activation of the sympathetic nervous system. One pivotal region controlling arterial pressure set point is nucleus tractus solitarii (NTS). We recently identified that pro-inflammatory molecules, such as junctional adhesion molecule-1, were over expressed in endothelial cells of the microvasculature supplying the NTS in an animal model of human hypertension (the spontaneously hypertensive rat: SHR) compared to normotensive Wistar Kyoto (WKY) rats. We have also shown endogenous leukocyte accumulation inside capillaries within the NTS of SHR but not WKY rats. Despite the inflammatory state in the NTS of SHR, transcripts of some inflammatory molecules such as chemokine (C-C motif) ligand 5 (Ccl5), and its receptors, chemokine (C-C motif) receptor 1 and 3 were down-regulated in the NTS of SHR compared to WKY rats. This may be compensatory to avoid further strong inflammatory activity. More importantly, we found that down-regulation of Ccl5 in the NTS of SHR may be pro-hypertensive since microinjection of Ccl5 into the NTS of SHR decreased arterial pressure but was less effective in WKY rats. Leukocyte accumulation of the NTS microvasculature may also induce an increase in vascular resistance and hypoperfusion within the NTS; the latter may trigger release of pro-inflammatory molecules which via paracrine signaling may affect central neural cardiovascular activity conducive to neurogenic hypertension. All told, we suggest that vascular inflammation within the brainstem contributes to neurogenic hypertension by multiple pathways.


Assuntos
Tronco Encefálico/fisiologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Inflamação Neurogênica/patologia , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologia , Animais , Pressão Sanguínea/fisiologia , Tronco Encefálico/patologia , Humanos , Hipertensão/etiologia , Inflamação/etiologia , Inflamação/patologia , Inflamação/fisiopatologia , Inflamação Neurogênica/etiologia , Inflamação Neurogênica/fisiopatologia , Núcleo Solitário/patologia , Núcleo Solitário/fisiologia , Doenças Vasculares/etiologia
14.
J Hypertens ; 29(4): 732-40, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21358418

RESUMO

OBJECTIVES: Recent studies have demonstrated that pro-inflammatory molecules such as junctional adhesion molecules-1 are highly expressed in the nucleus tractus solitarii (NTS) of the spontaneously hypertensive rat (SHR), compared to normotensive rats (Wistar-Kyoto rats: WKY), suggesting that the NTS of SHR may exhibit an abnormal inflammatory state. In the present study, we tested whether gene expression of inflammatory markers such as cytokines and chemokines is altered in the NTS of SHR and whether this contributes to the hypertensive phenotype in the SHR. METHODS: We have performed RT Profiler PCR arrays in the NTS of SHR and WKY, which were designed to specifically target major cytokines/chemokines and their receptors. To validate PCR array results quantitative RT-PCR was performed. Microinjection studies using anesthetized rats were also carried out to examine whether validated inflammatory molecules exhibit functional roles on cardiovascular regulation at the level of the NTS. RESULTS: Five inter-related transcripts were identified to be differentially expressed between the NTS of SHR and WKY. They include chemokine (C-C motif) ligand 5 (Ccl5), and its receptors, chemokine (C-C motif) receptor 1 and 3. All of them were down-regulated in the NTS of SHR compared to WKY. Moreover, we found that the protein Ccl5 microinjected into the NTS significantly decreased baseline arterial pressure and that the response was greater in the SHR compared to the WKY (-33.2±3.2 vs. -8.8±1.6 mmHg, P<0.001), demonstrating that its down-regulation in the NTS may contribute to hypertension in the SHR. CONCLUSION: We suggest that gene expression of specific chemokines may be down-regulated to protect further inflammatory reactions in the NTS of SHR at the expense of arterial hypertension.


Assuntos
Quimiocina CCL5/metabolismo , Regulação para Baixo , Hipertensão/genética , Animais , Perfilação da Expressão Gênica , Imuno-Histoquímica , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
PLoS One ; 6(2): e17339, 2011 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-21364960

RESUMO

BACKGROUND: The loss of diurnal rhythm in blood pressure (BP) is an important predictor of end-organ damage in hypertensive and diabetic patients. Recent evidence has suggested that two major physiological circadian rhythms, the metabolic and cardiovascular rhythms, are subject to regulation by overlapping molecular pathways, indicating that dysregulation of metabolic cycles could desynchronize the normal diurnal rhythm of BP with the daily light/dark cycle. However, little is known about the impact of changes in metabolic cycles on BP diurnal rhythm. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that feeding-fasting cycles could affect the diurnal pattern of BP, we used spontaneously hypertensive rats (SHR) which develop essential hypertension with disrupted diurnal BP rhythms and examined whether abnormal BP rhythms in SHR were caused by alteration in the daily feeding rhythm. We found that SHR exhibit attenuated feeding rhythm which accompanies disrupted rhythms in metabolic gene expression not only in metabolic tissues but also in cardiovascular tissues. More importantly, the correction of abnormal feeding rhythms in SHR restored the daily BP rhythm and was accompanied by changes in the timing of expression of key circadian and metabolic genes in cardiovascular tissues. CONCLUSIONS/SIGNIFICANCE: These results indicate that the metabolic cycle is an important determinant of the cardiovascular diurnal rhythm and that disrupted BP rhythms in hypertensive patients can be normalized by manipulating feeding cycles.


Assuntos
Fenômenos Fisiológicos Cardiovasculares , Ritmo Circadiano/fisiologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Fenômenos Fisiológicos Cardiovasculares/genética , Ritmo Circadiano/genética , Jejum/metabolismo , Jejum/fisiologia , Comportamento Alimentar/fisiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Gluconeogênese/genética , Frequência Cardíaca/fisiologia , Hipertensão/genética , Lipogênese/genética , Masculino , Metabolismo/genética , Metabolismo/fisiologia , Fotoperíodo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
16.
Auton Neurosci ; 162(1-2): 15-23, 2011 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-21334266

RESUMO

Since the nucleus tractus solitarii (NTS) is a pivotal region for regulating the set-point of arterial pressure, we propose here its role in the development of neurogenic hypertension. Given the findings of recent studies suggesting that the NTS of spontaneously hypertensive rats (SHR) exhibits a specific inflammatory state characterized by leukocyte accumulation within the NTS microvasculature, we hypothesized that gene expression levels of apoptotic factors are altered in the NTS of SHR compared to normotensive Wistar-Kyoto rats (WKY). To test this hypothesis, we used RT(2) Profiler PCR arrays targeting apoptosis-related factors. We found that gene expression of the death receptor Fas (tumor necrosis factor receptor superfamily, member 6) and the cysteine-aspartic acid protease caspase 12 were down-regulated in the NTS of both adult hypertensive and young pre-hypertensive SHR compared to age-matched WKY. On the other hand, an anti-apoptotic factor, neuronal apoptosis inhibitory protein, was highly increased in the NTS of SHR. These results suggest that the NTS of SHR exhibits an anti-apoptotic condition. Furthermore, this profile appears not to be secondary to hypertension. Whether this differential gene expression in the NTS contributes to the hypertensive state of the SHR via alteration of neuronal circuitry regulating cardiovascular autonomic activity awaits elucidation.


Assuntos
Apoptose/fisiologia , Núcleo Solitário/patologia , Animais , Pressão Sanguínea/fisiologia , Western Blotting , Química Encefálica/genética , Química Encefálica/fisiologia , Caspase 12/genética , Caspase 12/metabolismo , Interpretação Estatística de Dados , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Perfilação da Expressão Gênica , Imuno-Histoquímica , Masculino , Bulbo/metabolismo , Proteína Inibidora de Apoptose Neuronal/biossíntese , Proteína Inibidora de Apoptose Neuronal/genética , RNA/biossíntese , RNA/genética , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sistema Nervoso Simpático/fisiologia
17.
Am J Physiol Regul Integr Comp Physiol ; 298(1): R183-90, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19907006

RESUMO

Recent gene array and molecular studies have suggested that an abnormal gene expression profile of interleukin-6 (IL-6) in the nucleus tractus solitarii (NTS), a pivotal region for regulating arterial pressure, may be related to the development of neurogenic hypertension. However, the precise functional role of IL-6 in the NTS remains unknown. In the present study, we have tested whether IL-6 affects cardiovascular control at the level of the NTS. IL-6 (1, 10, and 100 fmol) was microinjected in the NTS of Wistar rats (280-350 g) under urethane anesthesia. Although the baseline levels of arterial pressure and heart rate did not change following IL-6 injections, the cardiac baroreflex in response to increased arterial pressure was dose-dependently attenuated. In addition, IL-6 (100 fmol) microinjections also attenuated l-glutamate-induced bradycardia at the level of the NTS. Immunohistochemical detection of IL-6 in naïve rats demonstrated that it was predominantly observed in neurons within the brain stem, including the NTS. These findings suggest that IL-6 within the NTS may play an important role for regulating cardiovascular control via modulation of input signals from baroreceptor afferents. Whether the abnormal gene expression of IL-6 in the NTS is associated in a causal way with hypertension remains to be resolved.


Assuntos
Barorreflexo/efeitos dos fármacos , Coração/fisiologia , Interleucina-6/farmacologia , Núcleo Solitário/efeitos dos fármacos , Animais , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Interleucina-6/administração & dosagem , Interleucina-6/metabolismo , Masculino , Microinjeções , Modelos Animais , Ratos , Ratos Wistar , Núcleo Solitário/metabolismo
18.
Exp Physiol ; 95(5): 595-600, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-19923159

RESUMO

Since the nucleus tractus solitarii (NTS) is a pivotal region for regulating the set-point of arterial pressure, we proposed a role for it in the development of neurogenic hypertension. Recent studies have suggested that proinflammatory molecules, such as junctional adhesion molecule 1 (JAM-1) are highly expressed in the NTS of an animal model of human essential hypertension, the spontaneously hypertensive rat (SHR), compared with normotensive rats (Wistar-Kyoto, WKY). Moreover, we have also shown endogenous leukocyte accumulation inside capillaries within the NTS of SHR but not WKY rats. Based on this evidence, we hypothesized that gene expression of cytokines/chemokines is altered in the NTS of SHR. We have screened for abnormally expressed inflammatory mediators in the NTS of SHR using the RT2 Profiler PCR arrays, which were designed specifically to target major cytokines/chemokines. The specific PCR array revealed that seven genes were less expressed in the NTS of SHR compared with WKY rats (more than twofold differences), while only two genes were more expressed in the SHR. Moreover, we identified that some of these validated molecules exhibit important functional roles for cardiovascular homeostasis at the level of the NTS. We suggest that abnormal gene expression of proinflammatory molecules, such as JAM-1, causes leukocyte accumulation within the vasculature in the NTS of SHR. Consequently, gene expression of specific cytokines/chemokines may be downregulated to avoid further strong inflammatory activity in the NTS of SHR at the expense of an alteration in neuronal activity that leads to cardiovascular autonomic pathology. Importantly, to allow translation of our work, these novel insights need to be assessed in hypertensive human brainstem tissue; their confirmation could lead to novel therapeutic approaches for one of the world's most prevalent diseases.


Assuntos
Citocinas/genética , Hipertensão/fisiopatologia , Núcleo Solitário/fisiopatologia , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/fisiologia , Modelos Animais de Doenças , Regulação para Baixo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
19.
Exp Physiol ; 94(7): 773-84, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19297387

RESUMO

Although both alpha(1)- and alpha(2)-adrenergic receptors (ARs) are known to be expressed in the nucleus of the solitary tract (NTS), the functional significance of these receptors is still not fully established. In this study, we microinjected alpha(1)- and alpha(2)-AR agonists into the NTS of urethane-anaesthetized Wister rats to study the cardiovascular effects in response to their activation. When the alpha(1)-AR agonist phenylephrine was microinjected into the area where barosensitive neurons are dominantly located (baro-NTS), mean arterial pressure (MAP) and heart rate (HR) were significantly elevated. When tested in the area where chemosensitive neurons are dominantly located (chemo-NTS), however, MAP and HR were significantly decreased. Pretreatment with the non-specific alpha-AR antagonist phentolamine into the NTS inhibited the phenylephrine-induced cardiovascular responses. In contrast, microinjection of the alpha(2)-AR agonist clonidine into either the baro-NTS or the chemo-NTS decreased MAP and HR; they were also inhibited by the alpha(2)-adrenergic antagonist yohimbine. Moreover, we immunohistochemically identified that cardiovascular responses induced by alpha(1)-ARs may be mediated by NTS neurons while those induced by alpha(2)-ARs may be mediated by astrocytes located in the barosensitive and chemosensitive areas of the NTS. These results suggest that both types of alpha-AR expressed in the NTS may be involved in regulating cardiovascular homeostasis via modulation of input signals from baroreceptor and chemoreceptor afferents; however, cardiovascular responses produced by stimulation of alpha(1)-ARs are strictly location specific within the NTS.


Assuntos
Receptores Adrenérgicos alfa/fisiologia , Núcleo Solitário/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Células Quimiorreceptoras/efeitos dos fármacos , Células Quimiorreceptoras/fisiologia , Clonidina/farmacologia , Perfilação da Expressão Gênica , Frequência Cardíaca/efeitos dos fármacos , Fentolamina/farmacologia , Fenilefrina/farmacologia , Pressorreceptores/efeitos dos fármacos , Pressorreceptores/fisiologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 2/genética , Núcleo Solitário/efeitos dos fármacos , Ioimbina/farmacologia
20.
Auton Neurosci ; 142(1-2): 25-31, 2008 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-18722165

RESUMO

Human essential hypertension is a complex polygenic trait with underlying genetic components that remain unknown. Since the brainstem structure--the nucleus of the solitary tract (NTS)--is a pivotal region for regulating the set-point of arterial pressure, we proposed a role for it in the development of primary hypertension. Using microarray and real-time RT-PCR, we have recently identified that some pro-inflammatory molecules, such as junctional adhesion molecule-1 (JAM-1; a leukocyte/platelet adhesion molecule), were over expressed in endothelial cells in the NTS of an animal model of human essential hypertension--the spontaneously hypertensive rat (SHR) compared to normotensive Wistar Kyoto rats (WKY). Adenoviral mediated over expression of JAM-1 in NTS of WKY rats produced both hypertension and localized leukocyte adherence to the microvasculature. With a known effect of leukocyte adhesion causing cytokine release, we predicted differences in the level of gene expression of cytokines in the NTS of SHR relative to WKY. Gene expression of monocyte chemoattractant protein-1 (MCP-1) was higher in the NTS of SHR while inter-leukin-6 (IL-6) was lower in the NTS of SHR compared to the WKY. Because both inflammatory molecules are known to affect neural functions, our data suggest that the microvasculature of NTS of the SHR exhibits a specific inflammatory state. We propose a new hypothesis that as a consequence of enhanced expression of leukocyte adhesion molecules within the microvasculature of NTS there is a specific inflammatory response that leads to cardiovascular autonomic dysfunction contributing to neurogenic hypertension.


Assuntos
Encefalite/imunologia , Hipertensão/imunologia , Núcleo Solitário/imunologia , Animais , Adesão Celular/genética , Adesão Celular/imunologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Quimiocina CCL2/genética , Quimiotaxia de Leucócito/genética , Modelos Animais de Doenças , Humanos , Interleucina-6/genética , Ratos , Ratos Endogâmicos SHR
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