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1.
PLoS One ; 15(5): e0226539, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413046

RESUMO

A murine model to study the effect of cold-induced stress (CIS) on Chlamydia muridarum genital infection and immune response has been developed in our laboratory. Previous results in the lab show that CIS increases the intensity of chlamydia genital infection, but little is known about the effects and mechanisms of CIS on the differentiation and activities of CD4+ T cell subpopulations and bone marrow-derived dendritic cells (BMDCs). The factors that regulate the production of T helper 1 (Th1) or T helper 2 (Th2) cytokines are not well defined. In this study, we examined whether CIS modulates the expressions of beta-adrenergic receptor (ß-AR), transcription factors, hallmark cytokines of Th1 and Th2, and differentiation of BMDCs during C. muridarum genital infection in the murine model. Our results show that the mRNA level of the beta2-adrenergic receptor (ß2-AR) compared to ß1-AR and ß3-AR was high in the mixed populations of CD4+ T cells and BMDCs. Furthermore, we observed decreased expression of T-bet, low level of Interferon-gamma (IFN-γ) production, increased expression of GATA-3, and Interleukin-4 (IL-4) production in CD4+ T cells of stressed mice. Exposure of BMDCs to Fenoterol, ß2-AR agonist, or ICI118,551, ß2-AR antagonist, revealed significant ß2-AR stimulation or inhibition, respectively, in stressed mice. Moreover, co-culturing of mature BMDCs and naïve CD4+ T cells increased the production of IL-4, IL-10, L-17, and IL-23 cytokines, suggesting that stimulation of ß2-AR leads to the increased production of Th2 cytokines. Overall, our results show for the first time that CIS promotes the switching from a Th1 to Th2 cytokine environment. This was evidenced in the murine stress model by the overexpression of GATA-3 concurrent with elevated IL-4 production, reduced T-bet expression, and IFN-γ secretion.


Assuntos
Infecções por Chlamydia/imunologia , Resposta ao Choque Frio , Células Th1/imunologia , Células Th2/imunologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Células Cultivadas , Chlamydia muridarum , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Fenoterol/farmacologia , Interferon gama/genética , Interferon gama/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Propanolaminas/farmacologia , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Nat Commun ; 11(1): 1730, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32265443

RESUMO

Cold stimuli and the subsequent activation of ß-adrenergic receptor (ß-AR) potently stimulate adipose tissue thermogenesis and increase whole-body energy expenditure. However, systemic activation of the ß3-AR pathway inevitably increases blood pressure, a significant risk factor for cardiovascular disease, and, thus, limits its application for the treatment of obesity. To activate fat thermogenesis under tight spatiotemporal control without external stimuli, here, we report an implantable wireless optogenetic device that bypasses the ß-AR pathway and triggers Ca2+ cycling selectively in adipocytes. The wireless optogenetics stimulation in the subcutaneous adipose tissue potently activates Ca2+ cycling fat thermogenesis and increases whole-body energy expenditure without cold stimuli. Significantly, the light-induced fat thermogenesis was sufficient to protect mice from diet-induced body-weight gain. The present study provides the first proof-of-concept that fat-specific cold mimetics via activating non-canonical thermogenesis protect against obesity.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Channelrhodopsins/metabolismo , Obesidade/terapia , Optogenética/instrumentação , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Termogênese/efeitos da radiação , Adipócitos/efeitos da radiação , Tecido Adiposo/efeitos da radiação , Animais , Peso Corporal/fisiologia , Peso Corporal/efeitos da radiação , Cálcio/metabolismo , Células Cultivadas , Channelrhodopsins/efeitos da radiação , Channelrhodopsins/uso terapêutico , Dieta , Metabolismo Energético/efeitos da radiação , Locomoção , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Optogenética/métodos , Consumo de Oxigênio , Receptores Adrenérgicos beta/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Termogênese/fisiologia
3.
Sci China Life Sci ; 63(5): 697-705, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32246402

RESUMO

The Hippo pathway is a newly identified pathway and evolutionarily conserved from flies to humans mainly regulating cell proliferation. Transcriptional co-activator Yes-associated protein (YAP) functions as a major downstream effector and key node of the Hippo pathway. Phosphorylation of YAP is critical to regulate YAP activity and its corresponding functions. ß-adrenergic receptor (ß-AR), a typical G protein coupled receptor (GPCR), mediates proliferation in various cell types and regulates multiple physical and pathological processes. However, the role of ß-AR in regulating YAP remains elusive. Here, we report that ß-AR can obviously stimulate YAP tyrosine phosphorylation. The mechanism is that ß-AR stimulation results in tyrosine kinase Src activation and Src phosphorylates YAP tyrosine at Y357. Further studies demonstrate that inhibition of Src kinase activity can obviously alleviate ß-AR induced YAP tyrosine phosphorylation and cell proliferation. We conclude that ß-AR can induce YAP tyrosine phosphorylation and also establish the Src/YAP pathway as a critical signaling branch downstream of GPCR.


Assuntos
Receptores Adrenérgicos beta/metabolismo , Fatores de Transcrição/metabolismo , Quinases da Família src/metabolismo , Animais , Proliferação de Células , Fibroblastos/citologia , Regulação da Expressão Gênica , Células HEK293 , Coração , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Fosforilação , Ratos , Transfecção , Tirosina/metabolismo
4.
Circ Heart Fail ; 13(3): e006331, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32164435

RESUMO

BACKGROUND: Chronotropic incompetence is common in heart failure with preserved ejection fraction (HFpEF) and is associated with impaired aerobic capacity. We investigated the integrity of cardiac ß-receptor responsiveness, an important mechanism involved in exertional increases in HR, in HFpEF and control subjects. METHODS: Thirteen carefully screened patients with HFpEF and 13 senior controls underwent exercise testing and graded isoproterenol infusion to quantify cardiac ß-receptor-mediated HR responses. To limit autonomic neural influences on heart rate (HR) during isoproterenol, dexmedetomidine and glycopyrrolate were given. Isoproterenol doses were increased incrementally until HR increased by 30 beats per minute. Plasma levels of isoproterenol at each increment were measured by liquid chromatography with electrochemical detection and plotted against HR. RESULTS: Peak VO2 and HR (117±15 versus 156±15 beats per minute; P<0.001) were lower in HFpEF than senior controls. Cardiac ß-receptor sensitivity was lower in HFpEF compared to controls (0.156±0.133 versus 0.254±0.166 beats per minute/[isoproterenol ng/mL]; P<0.001). Seven of 13 HFpEF subjects had ß-receptor sensitivity similar to senior controls but still had lower peak HRs (122±14 versus 156±15 beats per minute; P<0.001). CONCLUSIONS: Contrary to our hypothesis, patients with HFpEF displayed impaired cardiac ß-receptor sensitivity compared with senior controls. In the 7 out of 13 patients with HFpEF with age-appropriate ß-receptor sensitivity, peak HR remained low, suggesting impaired sinus node ß-receptor function may not fully account for low exercise HR response. Rather in some patients with HFpEF, chronotropic incompetence might reflect premature cessation of exercise before maximal sinus node activation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02524145.


Assuntos
Tolerância ao Exercício , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca , Receptores Adrenérgicos beta/metabolismo , Nó Sinoatrial/fisiopatologia , Volume Sistólico , Função Ventricular Esquerda , Adaptação Fisiológica , Agonistas Adrenérgicos beta/administração & dosagem , Idoso , Estudos de Casos e Controles , Teste de Esforço , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Humanos , Isoproterenol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Receptores Adrenérgicos beta/efeitos dos fármacos , Nó Sinoatrial/efeitos dos fármacos , Nó Sinoatrial/metabolismo , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
5.
Lancet Neurol ; 19(3): 247-254, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31999942

RESUMO

BACKGROUND: ß-adrenoceptors are widely expressed in different human organs, mediate important body functions and are targeted by medications for various diseases (such as coronary heart disease and heart attack) and many ß-adrenoceptor acting drugs are listed on the WHO Model List of Essential Medicines. ß-adrenoceptor antagonists are used by billions of patients with neurological disorders, primarily for the treatment of migraine and action tremor (mainly essential tremor), worldwide. RECENT DEVELOPMENTS: An observational study reported a link between the chronic use of the ß-adrenoceptor antagonist propranolol and an increased risk of Parkinson's disease, while the chronic use of the ß-adrenoceptor agonists was associated with a decreased risk. Further support of this association was provided by a dose-dependent decrease in the risk of Parkinson's disease with chronic ß-adrenoceptor agonist (eg, salbutamol) use, and by functional data indicating a possible underlying molecular mechanism. Five additional epidemiological studies have examined the modulation of the risk of Parkinson's disease as a result of the use of ß-adrenoceptor-acting drugs in different populations. Overall, similar estimates but different interpretations of the associations were provided. Several findings suggest that the increase in risk of Parkinson's disease associated with ß-adrenoceptor antagonists use can be explained by reverse causation because prodromal Parkinson's disease is often associated with non-specific action tremor, which is usually treated with propranolol. The lower risk of Parkinson's disease seen in patients receiving ß-adrenoceptor agonists is likely to be indirectly mediated by smoking because smoking has a strong inverse association with Parkinson's disease (people that smoke have a reduced risk of developing Parkinson's disease). Smoking also causes chronic obstructive pulmonary disease, which is treated with ß-adrenoceptor-agonist medications. Even if causal, the effect of ß-adrenoceptor antagonists on the risk of Parkinson's disease would be small compared with other Parkinson's disease risk factors and would be similar to the risk evoked by pesticide exposure. The estimated risk of Parkinson's disease because of ß-adrenoceptor antagonists use corresponds to one case in 10 000 patients after 5 years of propranolol use, and would be considered a very rare adverse effect. Thus, not using ß-adrenoceptor antagonists would severely harm patients with recommended indications, such as heart disease or migraine. Similarly, 50 000 people would have to be treated for 5 years with salbutamol to prevent Parkinson's disease in one patient, suggesting that primary preventive therapy studies on disease modification are not warranted. WHERE NEXT?: Epidemiological evidence for a causal relationship between use of ß2-adrenoceptor antagonists and the increased risk of Parkinson's disease is weak, with other explanations for the association being more probable. Future observational studies are warranted to clarify this association. However, given the very low risk associated with propranolol, most clinicians are unlikely to change their treatment approach.


Assuntos
Antagonistas Adrenérgicos beta/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Receptores Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos beta/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Propranolol/efeitos adversos , Propranolol/uso terapêutico , Fatores de Risco , Transdução de Sinais
6.
Nature ; 577(7792): 695-700, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31969708

RESUMO

Increased cardiac contractility during the fight-or-flight response is caused by ß-adrenergic augmentation of CaV1.2 voltage-gated calcium channels1-4. However, this augmentation persists in transgenic murine hearts expressing mutant CaV1.2 α1C and ß subunits that can no longer be phosphorylated by protein kinase A-an essential downstream mediator of ß-adrenergic signalling-suggesting that non-channel factors are also required. Here we identify the mechanism by which ß-adrenergic agonists stimulate voltage-gated calcium channels. We express α1C or ß2B subunits conjugated to ascorbate peroxidase5 in mouse hearts, and use multiplexed quantitative proteomics6,7 to track hundreds of proteins in the proximity of CaV1.2. We observe that the calcium-channel inhibitor Rad8,9, a monomeric G protein, is enriched in the CaV1.2 microenvironment but is depleted during ß-adrenergic stimulation. Phosphorylation by protein kinase A of specific serine residues on Rad decreases its affinity for ß subunits and relieves constitutive inhibition of CaV1.2, observed as an increase in channel open probability. Expression of Rad or its homologue Rem in HEK293T cells also imparts stimulation of CaV1.3 and CaV2.2 by protein kinase A, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Proteômica , Receptores Adrenérgicos beta/metabolismo , Animais , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo N/metabolismo , Microambiente Celular , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Células HEK293 , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Humanos , Masculino , Camundongos , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Miocárdio/metabolismo , Fosforilação , Domínios Proteicos , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Transdução de Sinais , Proteínas ras/química , Proteínas ras/metabolismo
7.
Life Sci ; 241: 117155, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837330

RESUMO

AIMS: ß-Adrenoceptors (ß-ADRs) mediating the relaxation of rat superior mesenteric arteries (SMAs) were pharmacologically identified, and the effects of chemical sympathetic denervation on ß-ADR-mediated relaxation were examined. MAIN METHODS: The tension changes of endothelium-denuded SMAs were isometrically recorded and the mRNA of endothelium-denuded SMA ß-ADR was detected using RT-PCR. KEY FINDINGS: In endothelium-denuded SMAs contracted with ≥10-7 M phenylephrine (an α1-ADR agonist), isoprenaline (a ß-ADR agonist)-induced relaxation was competitively inhibited by 3 × 10-9-10-8 M propranolol (a ß1,2-ADR antagonist), but not further affected by ≥10-8 M propranolol. Although isoprenaline-induced relaxation was not affected by ICI-118,551 (10-9-10-8 M; a ß2-ADR antagonist), it was competitively inhibited by atenolol (10-7-3 × 10-7 M; a ß1-ADR antagonist) in the presence of ICI-118,551. In the presence of 10-7 M propranolol, isoprenaline- and CGP-12177A (a ß3-ADR partial agonist)-induced relaxation was competitively inhibited by high concentrations of bupranolol (a ß1,2,3-ADR antagonist), with pA2 values of 6.49 and 5.76, respectively. We detected the mRNA of ß1- and ß3-ADRs in endothelium-denuded SMAs. Treatment with 6-hydroxydopamine (a catecholaminergic neurotoxin) reduced maximal isoprenaline-induced relaxation in the presence and absence of 10-7 M propranolol, but not CGP-12177A-induced relaxation. SIGNIFICANCE: Isoprenaline-induced relaxation of rat SMAs is mediated by ß1- and ß3-ADRs. ß-ADR-mediated relaxation of rat SMAs is shown to be attenuated by chemical sympathetic denervation. The differences in the effects of bupranolol and chemical sympathetic denervation on the responses to isoprenaline and CGP-12177A in rat SMAs might be explained by the possible presence of multiple ß3-ADRs with different pharmacological properties.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Artéria Mesentérica Superior/fisiologia , Relaxamento Muscular/fisiologia , Receptores Adrenérgicos beta/química , Receptores Adrenérgicos beta/metabolismo , Simpatectomia Química/métodos , Animais , Isoproterenol/farmacologia , Masculino , Artéria Mesentérica Superior/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Propanolaminas/farmacologia , Ratos , Ratos Wistar
8.
Surgery ; 167(2): 493-498, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31493902

RESUMO

BACKGROUND: Cardiac surgery and cardiopulmonary bypass are associated with alterations in blood pressure in the perioperative period, which, if uncontrolled, can result in end organ damage or dysfunction. Microvessels, significant contributors to blood pressure, both in the myocardium and peripheral skeletal muscle, have diminished responsiveness to major mediators of vascular tone, including thromboxane and serotonin after cardiopulmonary bypass. Responsiveness of these vessels to ß-adrenergic stimulation, a major mediator of vascular tone, has not yet been studied. In this report, we investigated the role of ß-adrenergic receptors in vascular tone regulation in human skeletal muscle microvessels before and after ß-adrenergic stimulation. METHODS: Skeletal muscle microvessels were isolated from patients undergoing cardiac surgery before and after cardiopulmonary bypass. Vessels were exposed in an ex vivo model to the ß-adrenergic agonist isoproterenol, or the direct adenylyl cyclase activator, forskolin, and the selective ß-receptor antagonist ICI18.551 hydrochloride plus isoproterenol. Immunofluorescence of ß receptors and Western blotting were also performed. RESULTS: Microvessels showed diminished responsiveness to isoproterenol (10-6 to 10-4M) after cardiopulmonary bypass (n = 8/group, P = .01). Pretreatment with the selective ß-2 blocker ICI18.551 (10-6M) prevented isoproterenol-induced microvascular relaxation (P = .001). Forskolin-induced relaxation response was also significantly diminished after cardiopulmonary bypass (n = 4/group, P < .05 versus before cardiopulmonary bypass). No significant changes in the total protein expression of ß-1, ß-2, and ß-3 receptors were detected by western blotting or immunofluorescence. CONCLUSION: Microvessels isolated from human skeletal muscle show diminished responsiveness to isoproterenol and its downstream activator forskolin after cardiopulmonary bypass, suggesting there is an alteration in ß-adrenergic receptor responsive in adenylate cyclase. The relaxation response to isoproterenol was via activation ß-2 receptors without changes in ß-adrenergic receptor abundance.


Assuntos
Arteríolas/metabolismo , Ponte Cardiopulmonar/efeitos adversos , Receptores Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos beta , Antagonistas Adrenérgicos beta , Idoso , Idoso de 80 Anos ou mais , Arteríolas/efeitos dos fármacos , Colforsina , Feminino , Humanos , Técnicas In Vitro , Isoproterenol , Masculino , Músculo Esquelético/irrigação sanguínea
9.
Invest Ophthalmol Vis Sci ; 60(15): 5059-5069, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31800964

RESUMO

Purpose: Beta-adrenergic receptor (AR) antagonists, like propranolol, inhibit angiogenesis in multiple ocular conditions through an unknown mechanism. We previously showed that propranolol reduces choroidal neovascularization (CNV) by decreasing interleukin-6 levels. Since macrophages are one of the central producers of interleukin-6, we examined whether macrophages are required for propranolol-driven inhibition of choroidal angiogenesis. Methods: We tested the anti-angiogenic properties of propranolol in the choroidal sprouting assay and the laser-induced CNV model. Bone marrow-derived monocytes (BMDMs) were added to the choroidal sprouting assay and Ccr2-/- mice were subjected to laser-induced CNV. Multi-parameter flow cytometry was performed to characterize the ocular mononuclear phagocyte populations after laser injury and during propranolol treatment. Results: Propranolol reduced choroidal angiogenesis by 41% (P < 0.001) in the choroidal sprouting assay. Similarly, propranolol decreased laser-induced CNV by 50% (P < 0.05) in female mice, with no change in males. BMDMs increased choroidal sprouting by 146% (P < 0.0001), and this effect was ablated by propranolol. Beta-AR inhibition had no effect upon laser-induced CNV area in female Ccr2-/- mice. MHCII+ and MHCII- macrophages increased 20-fold following laser treatment in wildtype mice as compared to untreated mice, and this effect was completely attenuated in lasered Ccr2-/- mice. Moreover, propranolol increased the numbers of MHCII+ and MHCII- macrophages by 1.9 (P = 0.07) and 3.1 (P < 0.05) fold in lasered female mice with no change in macrophage numbers in males. Conclusions: Our data suggest that propranolol inhibits angiogenesis through recruitment of monocyte-derived macrophages in female mice only. These data show the anti-angiogenic nature of beta-AR blocker-recruited monocyte-derived macrophages in CNV.


Assuntos
Neovascularização de Coroide/tratamento farmacológico , Angiofluoresceinografia/métodos , Macrófagos/patologia , Monócitos/patologia , Propranolol/farmacologia , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Corioide/metabolismo , Corioide/patologia , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Fundo de Olho , Imageamento Tridimensional , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Receptores Adrenérgicos beta/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia
10.
J Neuroinflammation ; 16(1): 266, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847911

RESUMO

BACKGROUND: The involvement of microglia in neuroinflammatory responses has been extensively demonstrated. Recent animal studies have shown that exposure to either acute or chronic stress induces robust microglial activation in the brain. In the present study, we investigated the underlying mechanism of brain microglial activation by acute stress. METHODS: We first looked at the spatial distribution of the noradrenaline (NA)-synthesizing enzyme, DBH (dopamine ß-hydroxylase), in comparison with NA receptors-ß1, ß2, and ß3 adrenergic receptors (ß1-AR, ß2-AR, and ß3-AR)-after which we examined the effects of the ß-blocker propranolol and α-blockers prazosin and yohimbine on stress-induced microglial activation. Finally, we compared stress-induced microglial activation between wild-type (WT) mice and double-knockout (DKO) mice lacking ß1-AR and ß2-AR. RESULTS: The results demonstrated that (1) microglial activation occurred in most studied brain regions, including the hippocampus (HC), thalamus (TM), and hypothalamus (HT); (2) within these three brain regions, the NA-synthesizing enzyme DBH was densely stained in the neuronal fibers; (3) ß1-AR and ß2-AR, but not ß3-AR, are detected in the whole brain, and ß1-AR and ß2-AR are co-localized with microglial cells, as observed by laser scanning microscopy; (4) ß-blocker treatment inhibited microglial activation in terms of morphology and count through the whole brain; α-blockers did not show such effect; (5) unlike WT mice, DKO mice exhibited substantial inhibition of stress-induced microglial activation in the brain. CONCLUSIONS: We demonstrate that neurons/microglia may interact with NA via ß1-AR and ß2-AR.


Assuntos
Encéfalo/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Norepinefrina/metabolismo , Receptores Adrenérgicos beta/metabolismo , Animais , Masculino , Camundongos , Camundongos Knockout , Angústia Psicológica , Ratos Endogâmicos F344 , Restrição Física , Estresse Fisiológico/fisiologia
11.
Reprod Biol Endocrinol ; 17(1): 95, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744506

RESUMO

BACKGROUND: Polycystic ovary syndrome is characterized by hyperactivity of the ovarian sympathetic nervous system, increases in the content and release of norepinephrine, as well as decreases in the number of ß-adrenoreceptors. In the present study, ß-adrenoreceptors in the ovaries of rats with polycystic ovary syndrome were blocked and analyzed the resultant effects on ovulation, hormone secretion and the enzymes responsible for the synthesis of catecholamines. METHODS: At 60 days of age, vehicle or estradiol valerate-treated rats were injected with propranolol [10- 4 M] into the ovarian bursas on oestrus day. The animals were sacrificed on the next day of oestrus, and the ovulation response, the steroid hormone levels in the serum and the immunoreactivity of tyrosine hydroxylase and dopamine ß-hydroxylase in the ovaries were measured. RESULTS: In animals with the induction of polycystic ovary syndrome and ß-adrenoreceptor blocking, ovulation was restored in more than half of the animals and resulted in decreased hyperandrogenism with respect to the levels observed in the estradiol valerate-treated group. Tyrosine hydroxylase and dopamine ß-hydroxylase were present in the theca cells of the growing follicles and the interstitial gland. Injection of propranolol restored the tyrosine hydroxylase and ovarian dopamine ß-hydroxylase levels in rats with polycystic ovary syndrome induction. CONCLUSIONS: The results suggest that a single injection into the ovarian bursas of propranolol, a nonselective antagonist of ß-adrenoreceptor receptors, decreases the serum testosterone concentration and the formation of ovarian cysts, improving the ovulation rate that accompanies lower levels of tyrosine hydroxylase and dopamine ß-hydroxylase in the ovary.


Assuntos
Ovulação/efeitos dos fármacos , Síndrome do Ovário Policístico/metabolismo , Propranolol/farmacologia , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Estradiol , Estro/efeitos dos fármacos , Estro/fisiologia , Feminino , Humanos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/fisiopatologia , Ratos , Testosterona/sangue , Tirosina 3-Mono-Oxigenase/metabolismo
12.
Int J Mol Sci ; 20(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31653119

RESUMO

Cardiac arrhythmias constitute a major health problem with a huge impact on mortality rates and health care costs. Despite ongoing research efforts, the understanding of the molecular mechanisms and processes responsible for arrhythmogenesis remains incomplete. Given the crucial role of Ca2+-handling in action potential generation and cardiac contraction, Ca2+ channels and Ca2+ handling proteins represent promising targets for suppression of ventricular arrhythmias. Accordingly, we report the different roles of Ca2+-handling in the development of congenital as well as acquired ventricular arrhythmia syndromes. We highlight the therapeutic potential of gene therapy as a novel and innovative approach for future arrhythmia therapy. Furthermore, we discuss various promising cellular and mitochondrial targets for therapeutic gene transfer currently under investigation.


Assuntos
Arritmias Cardíacas/patologia , Cálcio/metabolismo , Terapia Genética , Animais , Arritmias Cardíacas/terapia , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Humanos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Receptores Adrenérgicos beta/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
13.
Am J Physiol Renal Physiol ; 317(6): F1623-F1636, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31608673

RESUMO

Salt sensitivity of blood pressure is characterized by inappropriate sympathoexcitation and renal Na+ reabsorption during high salt intake. In salt-resistant animal models, exogenous norepinephrine (NE) infusion promotes salt-sensitive hypertension and prevents dietary Na+-evoked suppression of the Na+-Cl- cotransporter (NCC). Studies of the adrenergic signaling pathways that modulate NCC activity during NE infusion have yielded conflicting results implicating α1- and/or ß-adrenoceptors and a downstream kinase network that phosphorylates and activates NCC, including with no lysine kinases (WNKs), STE20/SPS1-related proline-alanine-rich kinase (SPAK), and oxidative stress response 1 (OxSR1). In the present study, we used selective adrenoceptor antagonism in NE-infused male Sprague-Dawley rats to investigate the differential roles of α1- and ß-adrenoceptors in sympathetically mediated NCC regulation. NE infusion evoked salt-sensitive hypertension and prevented dietary Na+-evoked suppression of NCC mRNA, protein expression, phosphorylation, and in vivo activity. Impaired NCC suppression during high salt intake in NE-infused rats was paralleled by impaired suppression of WNK1 and OxSR1 expression and SPAK/OxSR1 phosphorylation and a failure to increase WNK4 expression. Antagonism of α1-adrenoceptors before high salt intake or after the establishment of salt-sensitive hypertension restored dietary Na+-evoked suppression of NCC, resulted in downregulation of WNK4, SPAK, and OxSR1, and abolished the salt-sensitive component of hypertension. In contrast, ß-adrenoceptor antagonism attenuated NE-evoked hypertension independently of dietary Na+ intake and did not restore high salt-evoked suppression of NCC. These findings suggest that a selective, reversible, α1-adenoceptor-gated WNK/SPAK/OxSR1 NE-activated signaling pathway prevents dietary Na+-evoked NCC suppression, promoting the development and maintenance of salt-sensitive hypertension.


Assuntos
Hipertensão/metabolismo , Norepinefrina , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos beta/metabolismo , Sódio na Dieta/farmacologia
14.
Am J Physiol Heart Circ Physiol ; 317(6): H1258-H1271, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31603352

RESUMO

Brain-derived neurotrophic factor (BDNF) is upregulated in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli such as stress and hyperosmolality, and BDNF acting in the PVN plays a key role in elevating sympathetic activity and blood pressure. However, downstream mechanisms mediating these effects remain unclear. We tested the hypothesis that BDNF increases blood pressure, in part by diminishing inhibitory hypotensive input from nucleus of the solitary tract (NTS) catecholaminergic neurons projecting to the PVN. Male Sprague-Dawley rats received bilateral PVN injections of viral vectors expressing either green fluorescent protein (GFP) or BDNF and bilateral NTS injections of vehicle or anti-dopamine-ß-hydroxylase-conjugated saporin (DSAP), a neurotoxin that selectively lesions noradrenergic and adrenergic neurons. BDNF overexpression in the PVN without NTS lesioning significantly increased mean arterial pressure (MAP) in awake animals by 18.7 ± 1.8 mmHg. DSAP treatment also increased MAP in the GFP group, by 9.8 ± 3.2 mmHg, but failed to affect MAP in the BDNF group, indicating a BDNF-induced loss of NTS catecholaminergic hypotensive effects. In addition, in α-chloralose-urethane-anesthetized rats, hypotensive responses to PVN injections of the ß-adrenergic agonist isoprenaline were significantly attenuated by BDNF overexpression, whereas PVN injections of phenylephrine had no effect on blood pressure. BDNF treatment was also found to significantly reduce ß1-adrenergic receptor mRNA expression in the PVN, whereas expression of other adrenergic receptors was unaffected. In summary, increased BDNF expression in the PVN elevates blood pressure, in part by downregulating ß-receptor signaling and diminishing hypotensive catecholaminergic input from the NTS to the PVN.NEW & NOTEWORTHY We have shown that BDNF, a key hypothalamic regulator of blood pressure, disrupts catecholaminergic signaling between the NTS and the PVN by reducing the responsiveness of PVN neurons to inhibitory hypotensive ß-adrenergic input from the NTS. This may be occurring partly via BDNF-mediated downregulation of ß1-adrenergic receptor expression in the PVN and results in an increase in blood pressure.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipertensão/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Regulação para Baixo , Isoproterenol/farmacologia , Masculino , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/genética , Saporinas/farmacologia , Transmissão Sináptica
15.
J Drugs Dermatol ; 18(10): 1006-1010, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31584779

RESUMO

Pyogenic granuloma (PG) is an acquired vascular growth on the skin and mucous membranes. Even though PG is a benign tumor, treatment is required due to associated risk of ulceration and bleeding, cosmetic concerns, and the low likelihood of spontaneous regression. Treatment entails excisional surgery, cryotherapy, or electrocautery; recurrence however is a major problem. Beta-blockers became an attractive option for the treatment of vascular growths after it got approved for infantile hemangioma. PG was found to express beta adrenergic receptors, similarly to infantile hemangioma. Several publications have reported the use of oral and topical beta blockers such as timolol, propranolol, and betaxolol for the treatment of PG. In this study, we summarized the literature with regards to the effectiveness of topical beta blockers for the treatment of PG, and discussed all published case reports, case series, and open-label single arm trials. J Drugs Dermatol. 2019;18(10):1006-1010.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Granuloma Piogênico/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Administração Cutânea , Administração Oral , Betaxolol/uso terapêutico , Ensaios Clínicos como Assunto , Granuloma Piogênico/patologia , Humanos , Propranolol/uso terapêutico , Receptores Adrenérgicos beta/metabolismo , Recidiva , Pele/patologia , Dermatopatias/patologia , Timolol/uso terapêutico , Resultado do Tratamento
16.
J Vet Med Sci ; 81(10): 1509-1514, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31484844

RESUMO

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) acts to inhibit protein translation through phosphorylating a specific substrate, eEF2. We previously found that the increased eEF2K expression in mesenteric artery mediates hypertension development in spontaneously hypertensive rats. More recently, we have revealed that a selective eEF2K inhibitor, A484954 induced vasorelaxation via opening inward rectifier K+ channel and activating ß2-adrenergic receptor in smooth muscle of rat isolated mesenteric artery, which contributes to prevent noradrenaline-induced acute increase in blood pressure (BP). In this study, we further explored acute effects of A484954 on BP in rats, especially focusing the action on ß-adrenergic receptor. We also examined whether A484954 affects contraction and heart rate (HR) of isolated heart. BP and HR were measured by a carotid cannulation method in rats. Isometric contraction and HR in rat isolated atria were also measured pharmacologically. A484954 potentiated adrenaline-induced decrease in diastolic BP (DBP) but not increase in systolic BP (SBP). A484954 potentiated isoproterenol-induced decrease in DBP but not SBP. Contrastingly, A484954 prevented a non-ß-adrenergic receptor agonist, angiotensin II-induced increase in both SBP and DBP. In isolated left atria, A484954 caused contraction, which was prevented by a ß-adrenergic receptor antagonist, propranolol. In isolated right atria, A484954 increased HR. In conclusion, we for the first time demonstrated that A484954 potentiates ß-adrenergic receptor agonist-induced decrease in DBP possibly through vasorelaxation mediated via activating ß2-adrenergic receptor. It was also demonstrated that A484954 causes contraction of rat isolated heart via activating ß1-adrenergic receptor.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ciclopropanos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirrolidinas/farmacologia , Vasodilatação/efeitos dos fármacos , Antagonistas Adrenérgicos beta/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Determinação da Pressão Arterial , Frequência Cardíaca/efeitos dos fármacos , Masculino , Contração Miocárdica/efeitos dos fármacos , Propranolol/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/metabolismo
17.
Angiol Sosud Khir ; 25(3): 11-16, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31503242

RESUMO

The review contains the data on adrenergic mechanisms of regulation of pulmonary microvessels tonicity and endothelial permeability. On smooth muscle cells of pulmonary vessels there are postsynaptic α1A-, α1B-, α1D- and α2A-, α2B-, α2C-adrenoreceptors whose activation by norepinephrine induces vasoconstriction. Excitation of ß1- and ß2-subtypes of adrenoreceptors leads to vasodilatation, Activation of α1-2- and ß1-3-adrenoreceptors of the endothelium contributes to enhancement of nitric oxide synthesis. The resulting reaction of pulmonary microvessels in response to administration of catecholamines appears be determined by interaction of adrenergic mechanisms of regulation of tonicity of smooth muscle cells and synthesis of nitric oxide by the endothelium. Constrictor and dilator reactions of pulmonary venous vessels in response to activation of α- and ß-adrenoreceptors, respectively, are more pronounced than in pulmonary arteries and make a significant contribution to the shifts of pulmonary vascular resistance. Excitation of α2- and ß2-adrenoreceptors of endothelial cells of microvessels of the lungs contributes to a decrease in their permeability. In order to find out the role of adrenergic mechanisms in shifts of the capillary filtration coefficient in simulating various pathology of pulmonary circulation, it is necessary to carry out integral studies that would make it possible to evaluate alterations in macro- and microhaemodynamics of the lungs.


Assuntos
Adrenérgicos , Células Endoteliais , Microvasos , Receptores Adrenérgicos beta , Adrenérgicos/farmacologia , Endotélio , Permeabilidade , Receptores Adrenérgicos beta/metabolismo
18.
PLoS Biol ; 17(8): e3000412, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31369546

RESUMO

Lipid species patterns are conserved within cells to maintain physicochemical properties of membranes and cellular functions. We present the lipidome, including sterols, glycerolipids (GLs), glycerophospholipids (GPLs), and sphingolipids (SLs), of primary ex vivo differentiated (I) white, (II) brite, and (III) brown adipocytes derived from primary preadipocytes isolated from (I) epididymal white, (II) inguinal white, and (III) intrascapular brown adipose tissue. Quantitative lipidomics revealed significantly decreased fractions of phosphatidylcholine (PC) and phosphatidylethanolamine (PE), with longer (C > 36) and more polyunsaturated species, as well as lower levels of cardiolipin (CL) in white than in brite and brown adipocytes. Together, the brite and brown lipidome was comparable and indicates differences in membrane lipid packing density compared with white adipocytes. Changes in ceramide species profile could be related to the degree of browning. Beta-adrenergic stimulation of brown adipocytes led to generation of saturated lyso-PC (LPC) increasing uncoupling protein (UCP) 1-mediated leak respiration. Application of stable isotope labeling showed that LPC formation was balanced by an increased de novo synthesis of PC.


Assuntos
Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Adrenérgicos , Animais , Diferenciação Celular , Metabolismo dos Lipídeos/fisiologia , Lipidômica/métodos , Lipídeos/fisiologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
19.
Am J Physiol Cell Physiol ; 317(4): C674-C686, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31268780

RESUMO

G protein-coupled receptor kinase 2 (GRK2) is an important protein involved in ß-adrenergic receptor desensitization. In addition, studies have shown GRK2 can modulate different metabolic processes in the cell. For instance, GRK2 has been recently shown to promote mitochondrial biogenesis and increase ATP production. However, the role of GRK2 in skeletal muscle and the signaling mechanisms that regulate GRK2 remain poorly understood. Myostatin is a well-known myokine that has been shown to impair mitochondria function. Here, we have assessed the role of myostatin in regulating GRK2 and the subsequent downstream effect of myostatin regulation of GRK2 on mitochondrial respiration in skeletal muscle. Myostatin treatment promoted the loss of GRK2 protein in myoblasts and myotubes in a time- and dose-dependent manner, which we suggest was through enhanced ubiquitin-mediated protein loss, as treatment with proteasome inhibitors partially rescued myostatin-mediated loss of GRK2 protein. To evaluate the effects of GRK2 on mitochondrial respiration, we generated stable myoblast lines that overexpress GRK2. Stable overexpression of GRK2 resulted in increased mitochondrial content and enhanced mitochondrial/oxidative respiration. Interestingly, although overexpression of GRK2 was unable to prevent myostatin-mediated impairment of mitochondrial respiratory function, elevated levels of GRK2 blocked the increased autophagic flux observed following treatment with myostatin. Overall, our data suggest a novel role for GRK2 in regulating mitochondria mass and mitochondrial respiration in skeletal muscle.


Assuntos
Autofagia/efeitos dos fármacos , Quinase 2 de Receptor Acoplado a Proteína G/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mioblastos/efeitos dos fármacos , Miostatina/farmacologia , Animais , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Camundongos , Mitocôndrias/metabolismo , Células Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Miostatina/metabolismo , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
20.
Am J Physiol Endocrinol Metab ; 317(3): E535-E547, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237449

RESUMO

CB1 receptor (CB1R) antagonism improves the deleterious effects of a high-fat diet (HFD) by reducing body fat mass and adipocyte cell size. Previous studies demonstrated that the beneficial effects of the CB1R antagonist rimonabant (RIM) in white adipose tissue (WAT) are partially due to an increase of mitochondria numbers and upregulation thermogenesis markers, suggesting an induction of WAT beiging. However, the molecular mechanism by which CB1R antagonism induces weight loss and WAT beiging is unclear. In this study, we probed for genes associated with beiging and explored longitudinal molecular mechanisms by which the beiging process occurs. HFD dogs received either RIM (HFD+RIM) or placebo (PL) (HFD+PL) for 16 wk. Several genes involved in beiging were increased in HFD+RIM compared with pre-fat, HFD, and HFD+PL. We evaluated lipolysis and its regulators including natriuretic peptide (NP) and its receptors (NPRs), ß-1 and ß-3 adrenergic receptor (ß1R, ß3R) genes. These genes were increased in WAT depots, accompanied by an increase in lipolysis in HFD+RIM. In addition, RIM decreased markers of inflammation and increased adiponectin receptors in WAT. We observed a small but significant increase in UCP1; therefore, we evaluated the newly discovered UCP1-independent thermogenesis pathway. We confirmed that SERCA2b and RYR2, the two key genes involved in this pathway, were upregulated in the WAT. Our data suggest that the upregulation of NPRs, ß-1R and ß-3R, lipolysis, and SERCA2b and RYR2 may be one of the mechanisms by which RIM promotes beiging and overall the improvement of metabolic homeostasis induced by RIM.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores do Fator Natriurético Atrial/efeitos dos fármacos , Proteína Desacopladora 1/efeitos dos fármacos , Animais , Cães , Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Inflamação/prevenção & controle , Resistência à Insulina , Masculino , Biogênese de Organelas , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Rimonabanto/farmacologia , Termogênese/efeitos dos fármacos , Termogênese/genética , Perda de Peso/efeitos dos fármacos
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