RESUMO
Chronic intermittent hypoxia (CIH) is associated with diurnal hypertension, increased sympathetic nerve activity (SNA), and increases in circulating angiotensin II (ANG II). In rats, CIH increases angiotensin type 1 (AT1a) receptor expression in the median preoptic nucleus (MnPO), and pharmacological blockade or viral knockdown of this receptor prevents CIH-dependent increases in diurnal blood pressure. The current study investigates the role of AT1a receptor in modulating the activity of MnPO neurons following 7 days of CIH. Male Sprague-Dawley rats received MnPO injections of an adeno-associated virus with an shRNA against the AT1a receptor or a scrambled control. Rats were then exposed to CIH for 8 h a day for 7 days. In vitro, loose patch recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. In addition, MnPO K-Cl cotransporter isoform 2 (KCC2) protein expression was assessed using Western blot. CIH impaired the duration but not the magnitude of ANG II-mediated excitation in the MnPO. Both CIH and AT1a knockdown also impaired GABAA-mediated inhibition, and CIH with AT1a knockdown produced GABAA-mediated excitation. Recordings using the ratiometric Cl- indicator ClopHensorN showed CIH was associated with Cl- efflux in MnPO neurons that was associated with decreased KCC2 phosphorylation. The combination of CIH and AT1a knockdown attenuated reduced KCC2 phosphorylation seen with CIH alone. The current study shows that CIH, through the activity of AT1a receptors, can impair GABAA-mediated inhibition in the MnPO and contribute to sustained hypertension.
Assuntos
Pressão Sanguínea , Neurônios GABAérgicos/metabolismo , Hipertensão/metabolismo , Hipóxia/metabolismo , Inibição Neural , Área Pré-Óptica/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores de GABA-A/metabolismo , Síndromes da Apneia do Sono/metabolismo , Animais , Doença Crônica , Modelos Animais de Doenças , Hipertensão/genética , Hipertensão/fisiopatologia , Hipóxia/genética , Hipóxia/fisiopatologia , Masculino , Fosforilação , Área Pré-Óptica/fisiopatologia , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/fisiopatologia , Simportadores/metabolismo , Fatores de TempoRESUMO
There is limited knowledge on the occurrence of respiratory manifestations and sleep-disordered breathing in particular in children with the MECP2 duplication syndrome. Although sleep-disordered breathing and nocturnal hypoventilation are currently not cited as an important symptom in these children, we present three cases who all had an abnormal breathing during sleep. In view of the consequences associated with sleep apnea and hypoventilation, we advise to perform a polysomnography in children with MECP2 duplication. Different treatment modalities (ENT surgery, CPAP, and non-invasive ventilation) can be applied to successfully treat these conditions.
Assuntos
Hipoventilação/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Síndromes da Apneia do Sono/genética , Predisposição Genética para Doença , Humanos , Hipoventilação/diagnóstico por imagem , Hipoventilação/patologia , Lactente , Recém-Nascido , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico por imagem , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Síndromes da Apneia do Sono/diagnóstico por imagem , Síndromes da Apneia do Sono/patologiaRESUMO
Although snoring is common in the general population, its aetiology has been largely understudied. Here we report a genetic study on snoring (n ~ 408,000; snorers ~ 152,000) using data from the UK Biobank. We identify 42 genome-wide significant loci, with an SNP-based heritability estimate of ~10% on the liability scale. Genetic correlations with body mass index, alcohol intake, smoking, schizophrenia, anorexia nervosa and neuroticism are observed. Gene-based associations identify 173 genes, including DLEU7, MSRB3 and POC5, highlighting genes expressed in the brain, cerebellum, lungs, blood and oesophagus. We use polygenic scores (PGS) to predict recent snoring and probable obstructive sleep apnoea (OSA) in an independent Australian sample (n ~ 8000). Mendelian randomization analyses suggest a potential causal relationship between high BMI and snoring. Altogether, our results uncover insights into the aetiology of snoring as a complex sleep-related trait and its role in health and disease beyond it being a cardinal symptom of OSA.
Assuntos
Bancos de Espécimes Biológicos , Estudo de Associação Genômica Ampla , Fatores de Risco , Ronco/epidemiologia , Ronco/genética , Anorexia Nervosa , Índice de Massa Corporal , Proteínas de Transporte/genética , Demografia , Feminino , Regulação da Expressão Gênica , Loci Gênicos , Humanos , Estilo de Vida , Masculino , Análise da Randomização Mendeliana , Metionina Sulfóxido Redutases/genética , Proteínas de Neoplasias/genética , Neuroticismo , Polimorfismo de Nucleotídeo Único , Esquizofrenia , Síndromes da Apneia do Sono/genética , Transtornos do Sono-Vigília/genética , Fumar , Ronco/etiologia , Reino UnidoRESUMO
Interstitial microdeletions at chromosome 19p13.3 are frequently associated with a constellation of clinical features including macrocephaly, characteristic face, intellectual disability, and sleep apnea. Previous studies in 25 patients with 19p13.3 microdeletions have revealed loss of MAP2K2 in 24 patients and that of PIAS4 and ZBTB7A in 23 patients, suggesting that these three adjacent genes are candidate genes for the phenotypic development in 19p13.3 microdeletions. We identified a de novo likely pathogenic heterozygous missense variant of ZBTB7A (NM_015898.3:c.1152C>G, p.(Cys384Trp)) in a Japanese boy with macrocephaly, intellectual disability, and sleep apnea. This variant affects the conserved cysteine residue forming the coordinate bond with Zn2+ ion at the first zinc finger domain, and is predicted to exert a dominant-negative effect because of the generation of homo- and hetero-dimers with the wild-type and variant ZBTB7A proteins. The results argue for a critical relevance of ZBTB7A to the development of most, but probably not all, of the 19p13.3 microdeletion phenotype.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 19/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , MAP Quinase Quinase 2/genética , Megalencefalia/genética , Síndromes da Apneia do Sono/genética , Fatores de Transcrição/genética , Criança , Deleção Cromossômica , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , FenótipoRESUMO
Streptococcus pneumonia, one of the major colonizers in nasopharyngeal adenoids, has been the predominant pathogen causing acute otitis media (AOM) in children. Recent evidence suggests an association between IL-17A-mediated immune response and the clearance of pneumococcal colonization in nasopharyngeal adenoids. Here, we evaluated the expressions of IL-17A and associated genes in hypertrophic adenoid tissues of children with sleep-disordered breathing (SDB) and otitis media with effusion (OME) and their association with pneumococcal carriage. Sixty-six pediatric patients with adenoid hypertrophy were enrolled. During adenoidectomy, nasopharyngeal swab and adenoid tissues were used to determine pneumococcal carriage and IL-17A expression. Our results revealed significantly higher levels of IL-17A and IL-17A:IL-10 mRNA in the SDB patients positive for nasopharyngeal pneumococcal carriage than those negative. However, these differences were not significant in the OME group. These results suggested, in OME patients, prolonged or chronic pneumococcal carriage may occur because of insufficient IL-17A-mediated mucosal clearance, and could further lead to AOM and OME development.
Assuntos
Tonsila Faríngea/metabolismo , Interleucina-17/genética , Nasofaringe/metabolismo , Otite Média com Derrame/genética , Pneumonia Pneumocócica/genética , Síndromes da Apneia do Sono/genética , Tonsila Faríngea/microbiologia , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Humanos , Hipertrofia , Imuno-Histoquímica , Interleucina-17/metabolismo , Masculino , Nasofaringe/microbiologia , Nasofaringe/patologia , Otite Média com Derrame/metabolismo , Otite Média com Derrame/microbiologia , Pneumonia Pneumocócica/metabolismo , Pneumonia Pneumocócica/microbiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndromes da Apneia do Sono/metabolismo , Síndromes da Apneia do Sono/microbiologia , Streptococcus pneumoniae/fisiologiaRESUMO
Respiratory problems are common in Morquio-A syndrome (MPS IVA) but objective data on sleep-disordered breathing are scarce. The aim of our study was to review polygraphic (PG) findings and the need for noninvasive continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) in children with MPS IVA. A retrospective review of the clinical charts and PG of 16 consecutive children (7 boys, mean age 10.5 ± 4.2 years) with MPS IVA seen over a period of 3 years was performed. The prevalence of obstructive sleep apnea (OSA) was 69% with only five patients, all younger than 10 years old, having a normal PG. Four patients had mild OSA (apnea-hypopnea index [AHI] ≥1.5 and <5 events/hr), three patients had moderate OSA (AHI ≥5 and <10 events/hr), and three patients had severe OSA (AHI ≥ 10 events/hr). Among the 10 patients with OSA, 3 had prior adenoidectomy ± tonsillectomy and 6 were on enzyme replacement therapy. Only one patient had a central apnea index >5 events/hr despite prior cervico-occipital decompression. Six patients, all older than 11 years old, were started on CPAP or NIV because of severe OSA (n = 4), nocturnal hypoventilation (n = 1), or impossibility to be weaned from NIV after an acute respiratory failure (n = 1). Prevalence of OSA is high in patients with MPS IVA, underlying the importance of a systematic screening for sleep-disordered breathing. CPAP and NIV are efficient and well accepted for treating sleep-disordered breathing.
Assuntos
Mucopolissacaridose IV/diagnóstico , Síndromes da Apneia do Sono/diagnóstico , Adolescente , Adulto , Criança , Pressão Positiva Contínua nas Vias Aéreas , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Mucopolissacaridose IV/genética , Mucopolissacaridose IV/terapia , Estudos Retrospectivos , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/terapia , Tomografia Computadorizada por Raios X , Ventilação , Adulto JovemRESUMO
A 6-year-old girl had reduced fetal movements, numerous apneic spells, muscle hypotonia, and developmental motor delay. Her muscle biopsy tissue showed variation in myofiber diameters, small minicores by electron microscopy, and near-uniformity of type I fibers. Although no mutations were detected in RYR1, SEPN1, and DMPK genes, the RAPSN gene revealed one known mutation, p.Asn88Lys, from the mother, and one novel mutation, p.Cys366Gly, from the father. Life-saving pyridostigmine treatment suppressed her apneic spells and improved her motor development.
Assuntos
Músculo Esquelético/patologia , Síndromes da Apneia do Sono , Criança , Feminino , Humanos , Microscopia Eletrônica , Proteínas Musculares/genética , Músculo Esquelético/fisiopatologia , Músculo Esquelético/ultraestrutura , Mutação/genética , Síndromes Miastênicas Congênitas/complicações , Síndromes Miastênicas Congênitas/genética , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/patologia , Síndromes da Apneia do Sono/fisiopatologiaRESUMO
Obstructive sleep apnea (OSA) is a highly prevalent disease across the lifespan, is characterized by chronic intermittent hypoxia and sleep fragmentation, and has been independently associated with substantial cardiometabolic morbidity. However, the reversibility of end-organ morbidity with treatment is not always apparent, suggesting that both tissue remodeling and epigenetic mechanisms may be operationally involved. Here, we review the cumulative evidence focused around murine models of OSA to illustrate the temporal dependencies of cardiometabolic dysfunction and its reversibility, and more particularly to discuss the critical contributions of tissue macrophages to adipose tissue insulin resistance and vascular atherogenesis. In addition, we describe initial findings potentially implicating epigenetic alterations in both the emergence of the cardiometabolic morbidity of OSA, and in its reversibility with treatment. We anticipate that improved understanding of macrophage biology and epigenetics in the context of intermittent hypoxia and sleep fragmentation will lead to discovery of novel therapeutic targets and improved cardiovascular and metabolic outcomes in OSA.
Assuntos
Tecido Adiposo , Vasos Sanguíneos , Modelos Animais de Doenças , Epigênese Genética/fisiologia , Macrófagos/fisiologia , Camundongos , Síndromes da Apneia do Sono/patologia , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Vasos Sanguíneos/citologia , Vasos Sanguíneos/metabolismo , Polaridade Celular/fisiologia , Humanos , Macrófagos/metabolismo , Síndromes da Apneia do Sono/genéticaRESUMO
BACKGROUND: Deoxyribonucleic acid (DNA) methylation is an epigenetic modification involved in gene expression regulation, usually via gene silencing, which contributes to the risks of many multifactorial diseases. The aim of the present study was to analyze the influence of resting oxygen consumption on global and gene DNA methylation as well as protein secretion of inflammatory markers in blood cells from obese subjects with sleep apnea-hypopnea syndrome (SAHS). METHODS: A total of 44 obese participants with SAHS were categorized in 2 groups according to their resting oxygen consumption. DNA methylation levels were evaluated using a methylation-sensitive high resolution melting approach. RESULTS: The analyzed interleukin 6 (IL6) gene cytosine phosphate guanine (CpG) islands showed a hypomethylation, while serum IL-6 was higher in the low compared to the high oxygen consumption group (p < 0.05). Moreover, an age-related loss of DNA methylation of tumor necrosis factor (B = -0.82, 95% CI -1.33 to -0.30) and long interspersed nucleotide element 1 (B = -0.46; 95% CI -0.87 to -0.04) gene CpGs were found. Finally, studied CpG methylation levels of serpin peptidase inhibitor, clade E member 1 (r = 0.43; p = 0.01), and IL6 (r = 0.41; p = 0.02) were positively associated with fat-free mass. CONCLUSIONS: These findings suggest a potential role of oxygen in the regulation of inflammatory genes. Oxygen consumption measurement at rest could be proposed as a clinical biomarker of metabolic health.
Assuntos
Metilação de DNA , Interleucina-6/sangue , Obesidade/genética , Consumo de Oxigênio , Síndromes da Apneia do Sono/genética , Adiponectina/sangue , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Ilhas de CpG , Epigênese Genética , Regulação da Expressão Gênica , Hemodinâmica , Humanos , Interleucina-6/genética , Leptina/sangue , Elementos Nucleotídeos Longos e Dispersos/genética , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Inibidor 1 de Ativador de Plasminogênio/sangue , Inibidor 1 de Ativador de Plasminogênio/genética , Regiões Promotoras Genéticas , Serpinas/sangue , Serpinas/genética , Síndromes da Apneia do Sono/complicações , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genéticaRESUMO
Intermittent hypoxia (IH) induces activation of the integrated stress response (ISR), but its role in IH-induced visceral white adipose tissue (vWAT) insulin resistance is unknown. CHOP is activated by chronic ISR, whereas GADD34 dephosphorylates the subunit of translation initiation factor 2 (eIF2α), leading to termination of the ISR. We hypothesized that CHOP/Gadd34 null mice would not manifest evidence of insulin resistance after IH exposures. Eight-week-old CHOP/GADD34-/- (double mutant [DM]) and wild-type (WT) littermates were randomly assigned to IH or room air (RA) exposures for 6 weeks. Glucose and insulin tolerance tests were performed, and regulatory T cells (Tregs) and macrophages in vWAT were assessed. Phosphorylated eIF2α:total eIF2α, ATF4, XBP1 expression, and insulin-induced pAKT/AKT expression changes were examined in vWATs. Single GADD34-/- and PERK+/- mice were also evaluated. Body weight and vWAT mass were reduced in DM and WT mice after IH. M1/M2 macrophages and inflammatory macrophages (Ly-6chigh) were significantly increased in WT vWAT but remained unchanged in DM mice. Tregs were significantly decreased in WT vWAT but not in DM mice. Systemic insulin and glucose tolerance tests revealed insulin resistance in IH-WT but not in IH-DM mice. Similarly, decreased pAKT/AKT responses to exogenous insulin emerged in IH-WT compared with RA-WT mice, whereas no significant differences emerged in IH-DM compared with DM-RA. Chronic ISR activation appears to contribute to the insulin resistance and vWAT inflammation that characteristically emerge after long-term IH exposures in a murine model of obstructive sleep apnea.
Assuntos
Resistência à Insulina/genética , Gordura Intra-Abdominal , Macrófagos , Transdução de Sinais/genética , Síndromes da Apneia do Sono , Linfócitos T Reguladores , Animais , Modelos Animais de Doenças , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Gordura Intra-Abdominal/fisiopatologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Knockout , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/metabolismo , Síndromes da Apneia do Sono/patologia , Síndromes da Apneia do Sono/fisiopatologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismoRESUMO
We investigate the effects of intermittent hypoxia (IH), a characteristic feature of obstructive sleep apnea (OSA), on renal cancer progression in an animal and cell model. An in vivo mouse model (Balb/c, n = 50) of kidney cancer was used to assess the effect of IH on tumor growth, metastatic capacity, angiogenesis and tumor immune response. An in vitro model tested the effect of IH on RENCA cells, macrophages and endothelial cells. Tumor growth, metastatic capacity, circulating vascular endothelial growth factor (VEGF) and content of endothelial cells, tumor associated macrophages and their phenotype were assessed in the tumor. In vitro, VEGF cell expression was quantified.Although IH did not boost tumor growth, it significantly increased endothelial cells (p = 0.001) and circulating VEGF (p<0.001) in the in vivo model. Macrophages exposed to IH in vitro increased VEGF expression, whereas RENCA cells and endothelial cells did not. These findings are in keeping with previous clinical data suggesting that OSA has no effect on kidney cancer size and that the association observed between OSA and higher Fuhrman grade of renal cell carcinoma may be mediated though a proangiogenic process, with a key role of macrophages.
Assuntos
Hipóxia/complicações , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/complicações , Neovascularização Patológica/patologia , Síndromes da Apneia do Sono/complicações , Animais , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/patologia , Modelos Animais de Doenças , Hipóxia/genética , Hipóxia/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Macrófagos/patologia , Masculino , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Neovascularização Patológica/genética , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/patologia , Tela Subcutânea/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Sleep apnea, which is the periodic cessation of breathing during sleep, is a major health problem affecting over 10 million people in the United States and is associated with several sequelae, including hypertension and stroke. Clinical studies suggest that abnormal carotid body (CB) activity may be a driver of sleep apnea. Because gaseous molecules are important determinants of CB activity, aberrations in their signaling could lead to sleep apnea. Here, we report that mice deficient in heme oxygenase-2 (HO-2), which generates the gaseous molecule carbon monoxide (CO), exhibit sleep apnea characterized by high apnea and hypopnea indices during rapid eye movement (REM) sleep. Similar high apnea and hypopnea indices were also noted in prehypertensive spontaneously hypertensive (SH) rats, which are known to exhibit CB hyperactivity. We identified the gaseous molecule hydrogen sulfide (H2S) as the major effector molecule driving apneas. Genetic ablation of the H2S-synthesizing enzyme cystathionine-γ-lyase (CSE) normalized breathing in HO-2-/- mice. Pharmacologic inhibition of CSE with l-propargyl glycine prevented apneas in both HO-2-/- mice and SH rats. These observations demonstrate that dysregulated CO and H2S signaling in the CB leads to apneas and suggest that CSE inhibition may be a useful therapeutic intervention for preventing CB-driven sleep apnea.
Assuntos
Monóxido de Carbono/metabolismo , Gasotransmissores/metabolismo , Sulfeto de Hidrogênio/metabolismo , Síndromes da Apneia do Sono/metabolismo , Animais , Corpo Carotídeo/metabolismo , Corpo Carotídeo/fisiopatologia , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Feminino , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Respiração/genética , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/fisiopatologiaRESUMO
Sleep apnea is a risk factor for cardiovascular disease, and intermittent hypoxia (IH, 20 episodes/h of 5% O2-5% CO2 for 7 h/day) to mimic sleep apnea increases blood pressure and impairs hydrogen sulfide (H2S)-induced vasodilation in rats. The enzyme that produces H2S, cystathionine γ-lyase (CSE), is decreased in rat mesenteric artery endothelial cells (EC) following in vivo IH exposure. In silico analysis identified putative nuclear factor of activated T cell (NFAT) binding sites in the CSE promoter. Therefore, we hypothesized that IH exposure reduces Ca2+ concentration ([Ca2+]) activation of calcineurin/NFAT to lower CSE expression and impair vasodilation. In cultured rat aortic EC, inhibiting calcineurin with cyclosporine A reduced CSE mRNA, CSE protein, and luciferase activity driven by a full-length but not a truncated CSE promoter. In male rats exposed to sham or IH conditions for 2 wk, [Ca2+] in EC in small mesenteric arteries from IH rats was lower than in EC from sham rat arteries (Δfura 2 ratio of fluorescence at 340 to 380 nm from Ca2+ free: IH = 0.05 ± 0.02, sham = 0.17 ± 0.03, P < 0.05), and fewer EC were NFATc3 nuclear positive in IH rat arteries than in sham rat arteries (IH = 13 ± 3, sham = 59 ± 11%, P < 0.05). H2S production was also lower in mesenteric tissue from IH rats vs. sham rats. Endothelium-dependent vasodilation to acetylcholine (ACh) was lower in mesenteric arteries from IH rats than in arteries from sham rats, and inhibiting CSE with ß-cyanoalanine diminished ACh-induced vasodilation in arteries from sham but not IH rats but did not affect dilation to the H2S donor NaHS. Thus, IH lowers EC [Ca2+], NFAT activity, CSE expression and activity, and H2S production while inhibiting NFAT activation lowers CSE expression. The observations that IH exposure decreases NFATc3 activation and CSE-dependent vasodilation support a role for NFAT in regulating endothelial H2S production.NEW & NOTEWORTHY This study identifies the calcium-regulated transcription factor nuclear factor of activated T cells as a novel regulator of cystathionine γ-lyase (CSE). This pathway is basally active in mesenteric artery endothelial cells, but, after exposure to intermittent hypoxia to mimic sleep apnea, nuclear factor of activated T cells c3 nuclear translocation and CSE expression are decreased, concomitant with decreased CSE-dependent vasodilation.
Assuntos
Cistationina gama-Liase/biossíntese , Células Endoteliais/metabolismo , Hipóxia/metabolismo , Fatores de Transcrição NFATC/metabolismo , Acetilcolina/farmacologia , Animais , Sequência de Bases , Calcineurina/metabolismo , Cálcio/metabolismo , Células Cultivadas , Cistationina gama-Liase/genética , Sulfeto de Hidrogênio/metabolismo , Hipóxia/enzimologia , Masculino , Artérias Mesentéricas/citologia , Artérias Mesentéricas/metabolismo , Ratos , Ratos Sprague-Dawley , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/fisiopatologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Sleep apnea is a prevalent respiratory disease in which episodic cessation of breathing causes intermittent hypoxia. Patients with sleep apnea and rodents exposed to intermittent hypoxia exhibit hypertension. The carotid body senses changes in blood O2 concentrations, and an enhanced carotid body chemosensory reflex contributes to hypertension in sleep apnea patients. A rodent model of intermittent hypoxia that mimics blood O2 saturation profiles of patients with sleep apnea has shown that increased generation of reactive oxygen species (ROS) in the carotid body enhances the chemosensory reflex and triggers hypertension. CO generated by heme oxygenase-2 (HO-2) induces a signaling pathway that inhibits hydrogen sulfide (H2S) production by cystathionine γ-lyase (CSE), leading to suppression of carotid body activity. We found that ROS inhibited CO generation by HO-2 in the carotid body and liver through a mechanism that required Cys(265) in the heme regulatory motif of heterologously expressed HO-2. We showed that ROS induced by intermittent hypoxia inhibited CO production and increased H2S concentrations in the carotid body, which stimulated its neural activity. In rodents, blockade of H2S synthesis by CSE, by either pharmacologic or genetic approaches, inhibited carotid body activation and hypertension induced by intermittent hypoxia. Thus, our results indicate that oxidant-induced inactivation of HO-2, which leads to increased CSE-dependent H2S production in the carotid body, is a critical trigger of hypertension in rodents exposed to intermittent hypoxia.
Assuntos
Corpo Carotídeo/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hipertensão/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Síndromes da Apneia do Sono/metabolismo , Animais , Corpo Carotídeo/fisiopatologia , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/fisiopatologiaRESUMO
The carotid body (CB) plays an important role in the alteration of cardiorespiratory activity in chronic intermittent hypoxia (IH) associated with sleep-disordered breathing, which may be mediated by local expression of the renin-angiotensin system (RAS). We hypothesized a pathogenic role for IH-induced RAS expression in the CB. The CB expression of RAS components was examined in rats exposed to IH resembling a severe sleep-apnoeic condition for 7 days. In situ hybridization showed an elevated expression of angiotensinogen in the CB glomus cells in the hypoxic group when compared with the normoxic control group. Immunohistochemical studies and Western blot analysis revealed increases in the protein level of both angiotensinogen and angiotensin II type 1 (AT1) receptors in the hypoxic group, which were localized to the glomic clusters containing tyrosine hydroxylase. RT-PCR studies confirmed that levels of the mRNA expression of angiotensinogen, angiotensin-converting enzyme, AT1a and AT2 receptors were significantly increased in the CBs of the hypoxic rats. Functionally, the [Ca(2+)]i response to exogenous angiotensin II was enhanced in fura-2-loaded glomus cells dissociated from hypoxic rats when compared with those of the normoxic control animals. Pretreatment with losartan, but not PD123319, abolished the angiotensin II-induced [Ca(2+)]i response, suggesting an involvement of AT1 receptors. Moreover, daily treatment of the IH group of rats with losartan attenuated the levels of oxidative stress, gp91(phox) expression and macrophage infiltration in the CB. Collectively, the upregulated local RAS expression could play a pathogenic role in the augmented CB activity and local inflammation via AT1 receptor activation during IH conditions in patients with sleep-disordered breathing.
Assuntos
Corpo Carotídeo/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , Sistema Renina-Angiotensina/genética , Regulação para Cima/genética , Angiotensina II/genética , Angiotensina II/metabolismo , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Animais , Cálcio/metabolismo , Fura-2/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , NADPH Oxidase 2 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Estresse Oxidativo/genética , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
OBJECTIVE: To estimate the incidence of hospitalization for paediatric obstructive sleep apnoea syndrome (OSAS) or sleep-disordered breathing (SDB) caused by adenotonsillar or tonsillar hypertrophy without infection in children with a parent affected by OSAS. PATIENTS AND METHODS: Using the MigMed database at Lund University, hospital data on all children aged 0-18 years in Sweden between 1997 and 2007 (total of 3 million individuals) were used to identify all first hospital admissions for OSAS or either adenotonsillar or tonsillar hypertrophy. Next, individuals were categorized as either having or not having a parent affected by OSAS. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were estimated for boys and girls with a parent affected by OSAS. Children with OSAS or adenotonsillar or tonsillar hypertrophy without a parent affected by OSAS acted as the reference group (SIR=1). RESULTS: After accounting for socio-economic status, age, and geographic region, the SIRs of OSAS in boys and girls with a parent affected by OSAS were 3.09 (95% CI 1.83-4.90) and 4.46 (95% CI 2.68-6.98), respectively. The SIRs of adenotonsillar or tonsillar hypertrophy in boys and girls with a parent affected by OSAS were 1.82 (95% CI 1.54-2.14) and 1.56 (95% CI 1.30-1.87), respectively. CONCLUSION: This study indicates familial clustering of sleep-disordered breathing, which is important information for clinicians.
Assuntos
Saúde da Família , Hospitalização/estatística & dados numéricos , Síndromes da Apneia do Sono/epidemiologia , Síndromes da Apneia do Sono/genética , Tonsila Faríngea/patologia , Adolescente , Distribuição por Idade , Criança , Pré-Escolar , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Hipertrofia , Incidência , Lactente , Recém-Nascido , Masculino , Tonsila Palatina/patologia , Fatores de Risco , Distribuição por Sexo , Síndromes da Apneia do Sono/patologia , Suécia/epidemiologiaRESUMO
AIM: Caffeine treatment reduces the frequency of apnoea of prematurity (AOP) and eliminates the need for mechanical ventilation by acting as a nonspecific inhibitor of adenosine A1 and adenosine 2A receptors. Patients with AOP have demonstrated variant responses to caffeine therapy. We proposed to investigate the role of A1 and 2A polymorphisms in the development of AOP and individual differences in caffeine response. Secondly, we aimed to determine whether these polymorphisms have any effect on bronchopulmonary dysplasia (BPD) development. METHODS: Cord blood samples were collected from infants born with gestational ages between 24 and 34 weeks. Two groups were defined: patients without apnoea (n = 60) and patients with apnoea (n = 55). Patients with apnoea were divided into two subgroups: a caffeine-responsive group (n = 30) and an unresponsive group (n = 25). Six single-nucleotide polymorphisms were chosen for genotyping. RESULTS: Patients with apnoea over 28 weeks of gestational age who responded to the caffeine treatment were found to carry the rs16851030 C/C genotype rather than the C/T or T/T genotype. Logistic regression analysis showed a significant correlation between rs35320474-C/T and T/T genotypes and apnoea and BPD development. CONCLUSION: Our results indicate a role for adenosine receptor gene polymorphisms in susceptibility to AOP and BPD and in interindividual variability to caffeine response.
Assuntos
Cafeína/uso terapêutico , Citratos/uso terapêutico , Doenças do Prematuro/genética , Polimorfismo de Nucleotídeo Único , Antagonistas de Receptores Purinérgicos P1/uso terapêutico , Receptor A1 de Adenosina/genética , Receptores A2 de Adenosina/genética , Síndromes da Apneia do Sono/genética , Displasia Broncopulmonar/genética , Estudos de Casos e Controles , Esquema de Medicação , Marcadores Genéticos , Genótipo , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/tratamento farmacológico , Modelos Logísticos , Estudos Prospectivos , Síndromes da Apneia do Sono/tratamento farmacológico , Resultado do TratamentoRESUMO
Sleep-disordered breathing with recurrent apnea is associated with intermittent hypoxia (IH). Cardiovascular morbidities caused by IH are triggered by increased generation of reactive oxygen species (ROS) by pro-oxidant enzymes, especially NADPH oxidase-2 (Nox2). Previous studies showed that (i) IH activates hypoxia-inducible factor 1 (HIF-1) in a ROS-dependent manner and (ii) HIF-1 is required for IH-induced ROS generation, indicating the existence of a feed-forward mechanism. In the present study, using multiple pharmacological and genetic approaches, we investigated whether IH-induced expression of Nox2 is mediated by HIF-1 in the central and peripheral nervous system of mice as well as in cultured cells. IH increased Nox2 mRNA, protein, and enzyme activity in PC12 pheochromocytoma cells as well as in wild-type mouse embryonic fibroblasts (MEFs). This effect was abolished or attenuated by blocking HIF-1 activity through RNA interference or pharmacologic inhibition (digoxin or YC-1) or by genetic knockout of HIF-1α in MEFs. Increasing HIF-1α expression by treating PC 12 cells with the iron chelator deferoxamine for 20 h or by transfecting them with HIF-1alpha expression vector increased Nox2 expression and enzyme activity. Exposure of wild-type mice to IH (8 h/day for 10 days) up-regulated Nox2 mRNA expression in brain cortex, brain stem, and carotid body but not in cerebellum. IH did not induce Nox2 expression in cortex, brainstem, carotid body, or cerebellum of Hif1a(+/-) mice, which do not manifest increased ROS or cardiovascular morbidities in response to IH. These results establish a pathogenic mechanism linking HIF-1, ROS generation, and cardiovascular pathology in response to IH.
Assuntos
Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Glicoproteínas de Membrana/genética , NADPH Oxidases/genética , Espécies Reativas de Oxigênio/metabolismo , Síndromes da Apneia do Sono/metabolismo , Animais , Corpo Carotídeo/efeitos dos fármacos , Corpo Carotídeo/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/enzimologia , Desferroxamina/farmacologia , Digoxina/farmacologia , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Furanos/farmacologia , Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Indazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NADPH Oxidase 2 , Células PC12 , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/enzimologia , Ratos , Sideróforos/farmacologia , Síndromes da Apneia do Sono/genéticaRESUMO
O sono representa uma fase na qual o sistema respiratório sofre importantes mudanças que levam a uma maior vulnerabilidade e maior chance de ocorrência de anormalidades, mesmo em indivíduos normais. Na transição da vigília para o sono, existe normalmente um aumento da resistência de via aérea superior e prejuízo de diferentes respostas e reflexos protetores, os quais são eficientes em promover e manter a patência da via aérea superior durante a vigília. Em indivíduos que apresentam fatores de risco, tais como anormalidades anatômicas em via aérea superior, essas mudanças associadas ao sono não conseguem ser compensadas de forma eficaz e, com isso, ocorre uma maior chance de ocorrer um distúrbio respiratório do sono. Os distúrbios respiratórios do sono são caracterizados por diferentes graus de diminuição do espaço das vias aéreas superiores. Essa diminuição tem causas multifatoriais, que incluem anormalidades da anatomia de via aérea superior, alteração da resposta neuromuscular e de alterações em receptores de via aérea superior. Provavelmente muitas alterações funcionais e anatômicas em via aérea superior são de característica genética, tornando o individuo com maior risco quando exposto a determinados fatores ambientais, tais como alergias, e a partir da combinação destes fatores haverá uma maior chance de desenvolver distúrbios respiratórios do sono.
Sleep is a phase during which the respiratory system undergoes major changes. These changes lead to greater vulnerability and a greater risk of abnormalities, even in normal individuals. In the transition from wakefulness to sleep, there is commonly an increase in upper airway resistance and impairment of various protective responses and reflexes, which are efficient in promoting and maintaining upper airway patency during wakefulness. In individuals who present risk factors, such as anatomical abnormalities in the upper airway, these sleep-related changes cannot be efficaciously compensated, which increases the chances that sleep-disordered breathing will occur. Sleep-disordered breathing is characterized by a reduction in the size of upper airways, although the degree of the reduction varies. This reduction has multifactorial causes, which include anatomical abnormalities in the upper airway, alterations in the neuromuscular response and impairment of receptors in the upper airway. Upper airway functional and anatomical changes are likely to have genetic components, and, therefore, individuals exposed to certain environmental factors, such as allergies, have a greater chance of developing sleep-disordered breathing.
Assuntos
Humanos , Síndromes da Apneia do Sono/fisiopatologia , Sono/fisiologia , Fatores de Risco , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/prevenção & controleRESUMO
BACKGROUND: Telomere length (TL) in circulating leukocytes relates to the chronological age of the individual but it is believed to reflect also the cumulative burden of oxidative stress and inflammation over the life-time. Shortening of TL has been reported in several chronic conditions characterized by oxidative stress and inflammation, such as diabetes and atherosclerosis. Because these conditions also occur in patients with Obstructive Sleep Apnea Syndrome (OSAS), we hypothesized that TL would be reduced in patients with OSAS. METHODS: We compared TL in 256 patients with OSAS and 148 controls without OSAS. We also investigated if TL was related to the severity of OSAS, the presence of metabolic disorders and/or cardiovascular risk factors in these patients. RESULTS: TL was significantly shorter in patients with OSAS than in controls (p<0.001). This difference persisted after adjustment for age, body mass index, cholesterol, triglycerides, glucose, and uric acid levels, smoking status and the presence of arterial hypertension (p=0.018). TL was not related to the severity of OSAS as assessed by the apnea-hypopnea index, nocturnal oxygen saturation and daytime sleepiness. CONCLUSIONS: TL in circulating leukocytes is shorter in patients with OSAS than subjects without OSAS. The mechanism of this observation is unresolved since it appears independent of chronological age, the severity of OSAS and/or the presence of cardiovascular or metabolic alterations but the potential utility of TL as a biomarker of increased cardiovascular risk in these patients justifies further studies.