RESUMO
Altered sensitivity to the chronotropic and inotropic effects of catecholamines and reduction in ß1/ß2-adrenoceptor (ß1/ß2-AR) ratio were reported in failing and in senescent human heart, as well as in isolated atria and ventricle of rats submitted to stress. This was due to downregulation of ß1-AR with or without up-regulation of ß2-AR. AIMS: To investigate the stress-induced behavior of ß1-AR in the heart of mice expressing a non-functional ß2-AR subtype. The guiding hypothesis is that the absence of ß2-AR signaling will not affect the behavior of ß1-AR during stress and that those are independent processes. MATERIALS AND METHODS: The chronotropic and inotropic responses to ß-AR agonists in isolated atria of stressed mice expressing a non-functional ß2-AR were analyzed. The mRNA and protein expressions of ß1- and ß2-AR were also determined. KEY FINDINGS: No deaths were observed in mice under stress protocol. Atria of stressed mice displayed reduced sensitivity to isoprenaline compared to the controls, an effect that was abolished by the ß2- and ß1-AR antagonists 50 nM ICI118,551 and 300 nM CGP20712A, respectively. Sensitivity and maximum response to the ß-agonists dobutamine and salbutamol were not altered by stress or ICI118,551. The responses to dobutamine and salbutamol were prevented by CGP20712A. The expression of ß1-AR was reduced at protein levels. SIGNIFICANCE: Collectively, our data provide evidence that the cardiac ß2-AR is not essential for survival in a stressful situation and that the stress-induced reduction of ß1-AR expression was independent of the ß2-AR presence.
Assuntos
Agonistas Adrenérgicos beta , Dobutamina , Humanos , Camundongos , Ratos , Animais , Dobutamina/farmacologia , Dobutamina/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Átrios do Coração/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Isoproterenol/farmacologia , Isoproterenol/metabolismo , Albuterol/farmacologia , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/metabolismoRESUMO
The stress response is adaptive and aims to guarantee survival. However, the persistence of a stressor can culminate in pathology. Catecholamines released as part of the stress response over activate beta adrenoceptors (ß-AR) in the heart. Whether and how stress affects the expression of components of the intracellular environment in the heart is still, however, unknown. This paper used microarray to analyze the gene expression in the left ventricle wall of rats submitted to foot shock stress, treated or not treated with the selective ß2-AR antagonist ICI118,551 (ICI), compared to those of non-stressed rats also treated or not with ICI, respectively. The main findings were that stress induces changes in gene expression in the heart and that ß2-AR plays a role in this process. The vast majority of genes disregulated by stress were exclusive for only one of the comparisons, indicating that, in the same stressful situation, the profile of gene expression in the heart is substantially different when the ß2-AR is active or when it is blocked. Stress induced alterations in the expression of such a large number of genes seems to be part of stress-induced adaptive mechanism.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Regulação para Baixo/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Miocárdio/metabolismo , Estresse Fisiológico , Regulação para Cima/efeitos dos fármacos , Animais , Corticosterona/sangue , Ventrículos do Coração/efeitos dos fármacos , Sistema Imunitário/metabolismo , Masculino , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismoRESUMO
OBJECTIVE: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
Assuntos
Atenolol/uso terapêutico , Citocromo P-450 CYP2C9/genética , Regulação da Expressão Gênica , Losartan/uso terapêutico , Síndrome de Marfan/tratamento farmacológico , Receptores Adrenérgicos beta 1/genética , Adolescente , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Criança , Pré-Escolar , Citocromo P-450 CYP2C9/biossíntese , DNA/genética , Feminino , Seguimentos , Genótipo , Humanos , Lactente , Masculino , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Receptores Adrenérgicos beta 1/biossíntese , Estudos Retrospectivos , Adulto JovemRESUMO
Background The role of Ser49Gly beta1-adrenergic receptor genetic polymorphism (ADBR1-GP-Ser49Gly) as a predictor of death in heart failure (HF) is not established for the Brazilian population. Objectives To evaluate the association between ADBR1-GP-Ser49Gly and clinical outcomes in individuals with HF with reduced ejection fraction. Methods Secondary analysis of medical records of 178 patients and genotypes of GPRß1-Ser49Gly variants, classified as Ser-Ser, Ser-Gly and Gly-Gly. To evaluate their association with clinical outcome. A significance level of 5% was adopted. Results Cohort means were: clinical follow-up 6.7 years, age 63.5 years, 64.6% of men and 55.1% of whites. HF etiologies were predominantly ischemic (31.5%), idiopathic (23.6%) and hypertensive (15.7%). The genetic profile was distributed as follows: 122 Ser-Ser (68.5%), 52 Ser-Gly (28.7%) and 5 Gly-Gly (2.8%). There was a significant association between these genotypes and mean NYHA functional class at the end of follow-up (p = 0.014) with Gly-Gly being associated with less advanced NYHA. In relation to the clinical outcomes, there was a significant association (p = 0.026) between mortality and GPRß1-Ser49Gly: the number of deaths in patients with Ser-Gly (12) or Gly-Gly (1) was lower than in those with Ser-Ser (54). The Gly allele had an independent protective effect maintained after multivariate analysis and was associated with a reduction of 63% in the risk of death (p = 0.03; Odds Ratio 0.37 - CI 0.15-0.91). Conclusion The presence of ß1-AR-GP Gly-Gly was associated with better clinical outcome evaluated by NYHA functional class and was a predictor of lower risk of mortality, regardless of other factors, in a 6.7-year of follow-up. (Arq Bras Cardiol. 2020; 114(4):613-615).
Assuntos
Insuficiência Cardíaca , Polimorfismo Genético , Receptores Adrenérgicos beta 1/genética , Brasil , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Receptores AdrenérgicosRESUMO
Resumo Fundamento O papel do polimorfismo genético do receptor beta1-adrenérgico Ser49Gly (PG-Rβ1-Ser49Gly) como preditor de eventos na insuficiência cardíaca (IC) não está definido para a população brasileira. Objetivos Avaliar a relação entre PG-Rβ1-Ser49Gly e desfechos clínicos em indivíduos com IC com fração de ejeção reduzida. Métodos Análise secundária de prontuários de 178 pacientes e identificação das variantes do PG-Rβ1-Ser49Gly, classificadas como Ser-Ser, Ser-Gly e Gly-Gly. Avaliar sua relação com evolução clínica. Foi adotado nível de significância de 5%. Resultados As médias da coorte foram: seguimento clínico, 6,7 anos; idade, 64,4 anos; 63,5% de homens e 55,1% brancos. A etiologia da IC foi predominantemente isquêmica (31,5%), idiopática (23,6%) e hipertensiva (15,7%). O perfil genético teve a seguinte distribuição: 122 Ser-Ser (68,5%), 52 Ser-Gly (28,7%), e 5 Gly-Gly (2,8%). Houve relação significativa entre esses genótipos e a classe funcional da New York Heart Association (NYHA) ao final do acompanhamento (p = 0,014) com o Gly-Gly associado a NYHA menos avançada. Com relação aos desfechos clínicos, houve associação significativa (p = 0,026) entre mortalidade e PG-Rβ1-Ser49Gly: o número de óbitos em pacientes com Ser-Gly (12) ou Gly-Gly (1) foi menor que com Ser-Ser (54). O alelo Gly teve um efeito protetor independente mantido após análise multivariada e foi associado à redução na chance de óbito de 63% (p = 0,03; odds ratio 0,37 - IC 0,15 a 0,91). Conclusão A presença do PG-Rβ1 Gly-Gly associou-se a melhor evolução clínica avaliada pela classe funcional da NYHA e foi preditor de menor risco de mortalidade, independentemente de outros fatores, em seguimento de 6,7 anos. (Arq Bras Cardiol. 2020; 114(4):616-624)
Abstract Background The role of Ser49Gly beta1-adrenergic receptor genetic polymorphism (ADBR1-GP-Ser49Gly) as a predictor of death in heart failure (HF) is not established for the Brazilian population. Objectives To evaluate the association between ADBR1-GP-Ser49Gly and clinical outcomes in individuals with HF with reduced ejection fraction. Methods Secondary analysis of medical records of 178 patients and genotypes of GPRβ1-Ser49Gly variants, classified as Ser-Ser, Ser-Gly and Gly-Gly. To evaluate their association with clinical outcome. A significance level of 5% was adopted. Results Cohort means were: clinical follow-up 6.7 years, age 63.5 years, 64.6% of men and 55.1% of whites. HF etiologies were predominantly ischemic (31.5%), idiopathic (23.6%) and hypertensive (15.7%). The genetic profile was distributed as follows: 122 Ser-Ser (68.5%), 52 Ser-Gly (28.7%) and 5 Gly-Gly (2.8%). There was a significant association between these genotypes and mean NYHA functional class at the end of follow-up (p = 0.014) with Gly-Gly being associated with less advanced NYHA. In relation to the clinical outcomes, there was a significant association (p = 0.026) between mortality and GPRβ1-Ser49Gly: the number of deaths in patients with Ser-Gly (12) or Gly-Gly (1) was lower than in those with Ser-Ser (54). The Gly allele had an independent protective effect maintained after multivariate analysis and was associated with a reduction of 63% in the risk of death (p = 0.03; Odds Ratio 0.37 - CI 0.15-0.91). Conclusion The presence of β1-AR-GP Gly-Gly was associated with better clinical outcome evaluated by NYHA functional class and was a predictor of lower risk of mortality, regardless of other factors, in a 6.7-year of follow-up. (Arq Bras Cardiol. 2020; 114(4):613-615)
Assuntos
Humanos , Masculino , Feminino , Polimorfismo Genético , Receptores Adrenérgicos beta 1/genética , Insuficiência Cardíaca , Brasil , Receptores Adrenérgicos , Genótipo , Pessoa de Meia-IdadeRESUMO
BACKGROUND/AIMS: To investigate the role of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in renal ischemia/reperfusion-induced (I/R) cardiac inflammatoryprofile. METHODS: Left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 12 days, and treatment with or without atenolol, losartan, or enalapril. The expression of vimentin in kidney and atrial natriuretic factor (ANF) in the heart has been investigated by RT-PCR. In cardiac tissue, levels of ß1-adrenoreceptors, adenylyl cyclase, cyclic AMP-dependent protein kinase (PKA), noradrenaline, adrenaline (components of SNS), type 1 angiotensin II receptors (AT1R), angiotensinogen/Ang II and renin (components of RAS) have been measured by Western blotting and HPLC analysis. A panel of cytokines - tumour necrosis factor (TNF-α), interleukin IL-6, and interferon gamma (IFN-γ) - was selected as cardiac inflammatory markers. RESULTS: Renal vimentin mRNA levels increased by >10 times in I/R mice, indicative of kidney injury. ANF, a marker of cardiac lesion, increased after renal I/R, the values being restored to the level of Sham group after atenolol or enalapril treatment. The cardiac inflammatory profile was confirmed by the marked increase in the levels of mRNAs of TNF-α, IL-6, and IFN-γ. Atenolol and losartan reversed the upregulation of TNF-α expression, whereas enalapril restored IL-6 levels to Sham levels; both atenolol and enalapril normalized IFN-γ levels. I/R mice showed upregulation of ß1-adrenoreceptors, adenylyl cyclase, PKA and noradrenaline. Renal I/R increased cardiac levels of AT1R, which decreased after losartan or enalapril treatment. Renin expression also increased, with the upregulation returning to Sham levels after treatment with SNS and RAS blockers. Angiotensinogen/Ang II levels in heart were unaffected by renal I/R, but they were significantly decreased after treatment with losartan and enalapril, whereas increase in renin levels decreased. CONCLUSION: Renal I/R-induced cardiac inflammatory events provoked by the simultaneous upregulation of SNS and RAS in the heart, possibly underpin the mechanism involved in the development of cardiorenal syndrome.
Assuntos
Rim/metabolismo , Miocárdio/metabolismo , Sistema Renina-Angiotensina , Sistema Nervoso Simpático/metabolismo , Animais , Atenolol/farmacologia , Atenolol/uso terapêutico , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Catecolaminas/metabolismo , Enalapril/farmacologia , Enalapril/uso terapêutico , Interleucina-6/metabolismo , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Sistema Nervoso Simpático/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Vimentina/genética , Vimentina/metabolismoRESUMO
OBJECTIVE: The aim of the study was to investigate the expression patterns of a specific set of genes involved in the inflammation process in children with Down Syndrome (DS) and children without the syndrome (control group) to identify differences that may be related to the immune abnormalities observed in DS individuals. METHOD: RNA samples were obtained from peripheral blood, and gene expression was quantified using the TaqMan® Array Plate Human Inflammation Kit, which facilitated the investigation into 92 inflammation-related genes and four reference genes using real-time polymerase chain reaction (qPCR). RESULTS: Twenty genes showed differential expression in children with DS; 12 were overexpressed (PLA2G2D, CACNA1D, ALOX12, VCAM1, ICAM1, PLCD1, ADRB1, HTR3A, PDE4C, CASP1, PLA2G5, and PLCB4), and eight were underexpressed (LTA4H, BDKRB1, ADRB2, CD40LG, ITGAM, TNFRSF1B, ITGB1, and TBXAS1). After statistically correcting for the false discovery rate, only the genes BDKRB1 and LTA4H showed differential expression, and both were underexpressed within the DS group. CONCLUSION: DS children showed differential expression of inflammation-related genes that were not located on chromosome 21 compared with children without DS. The BDKRB1 and LTA4H genes may differentiate the case and control groups based on the inflammatory response, which plays an important role in DS pathogenesis.
Assuntos
Síndrome de Down/genética , Inflamação/genética , Proteínas Adaptadoras de Transdução de Sinal , Antígeno CD11b/genética , Canais de Cálcio Tipo L/genética , Caspase 1/genética , Criança , Pré-Escolar , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Síndrome de Down/imunologia , Feminino , Perfilação da Expressão Gênica , Fosfolipases A2 do Grupo II/genética , Fosfolipases A2 do Grupo V/genética , Humanos , Inflamação/imunologia , Molécula 1 de Adesão Intercelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/genética , Fosfolipase C beta/genética , Fosfolipase C delta/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Receptores 5-HT3 de Serotonina/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Proteínas Recombinantes de Fusão/genética , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
Numerous studies have evaluated the association between Arg389Gly polymorphism in the ß1 adrenergic receptor gene and heart failure risk. However, the specific association is still controversial. We performed a meta-analysis of all case-control studies that evaluated the association between Arg389Gly polymorphism and heart failure in humans. Studies were identified in the PubMed, Embase, and China National Knowledge Infrastructure databases. Two reviewers independently assessed the studies. Six case-control studies with a total of 1736 participants were included in the meta-analysis, including 882 cases with heart failure and 854 controls, and our results showed no association between the Arg389Gly polymorphism and heart failure [ArgArg vs GlyGly: odds ratio (OR) = 0.84, 95% confidence interval (CI) 0.59-1.20; ArgArg vs ArgGly: OR = 0.95, 95%CI 0.78-1.16; dominant model: OR = 1.08, 95%CI 0.89-1.31; recessive model: OR = 0.96, 95%CI 0.69-1.35]. No publication bias was found in the present study (all P values > 0.05). In conclusion, the ß1 adrenergic receptor gene Arg389Gly polymorphism might not be associated with heart failure risk. Further large and well-designed studies are needed to confirm this conclusion.
Assuntos
Predisposição Genética para Doença , Insuficiência Cardíaca/genética , Hipertensão/genética , Receptores Adrenérgicos beta 1/genética , China , Feminino , Estudos de Associação Genética , Insuficiência Cardíaca/patologia , Humanos , Hipertensão/patologia , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Cardiovascular diseases (CVD) have the highest worldwide mortality rate of any type of disease. In recent years, genetic research regarding CVD has been conducted using association studies, in which the presence of a genetic polymorphism associated with a specific cell signaling pathway in a lower or in a higher frequency among patients may be interpreted as a possible causal factor. Genetic polymorphisms that occur in the ß-adrenergic receptor 1 (ß-ADR1) can result in significant changes in its function that may result in physiopathologies. Ambiguous categorizations, such as skin color and self-reported ethnicity have been used in pharmacogenetic studies as phenotypic proxies for ancestry; however, admixed populations present a particular challenge to the effectiveness of this approach. The main objective of the present study was to estimate the diversity and the frequency of the Ser49Gly polymorphism of the ß-ADR1 gene in a sample of 188 male individuals from the population of Rio de Janeiro. The Ser49Gly frequencies were analyzed by two forms of sample stratification: The phenotypic criterion of black or non-black skin color, and African or non-African ancestry, defined using Y-chromosome single nucleotide polymorphisms and autosomal indel markers. These results were used to evaluate whether marker-based ancestry criteria and/or skin color were associated with the frequency of the Ser49Gly polymorphisms in the heterogeneous Rio de Janeiro/Brazilian population. The DNA fragments of interest were amplified by polymerase chain reaction with specific primers for the Ser49Gly marker, and genotyping reactions were performed by restriction with the enzyme Eco0109I. Heterozygosity values ranging from 0.25 to 0.50 and 0.20 to 0.41 were found for the groups stratified by ancestry and skin color, respectively. Using the Hardy-Weinberg equilibrium at the ser49Gly marker, it was found that there was no significant deviation in the genotype distribution of the whole Rio de Janeiro sample or the stratified sample. Analysis of the allelic distribution in the Rio de Janeiro population sample revealed frequencies of 80.30 and 19.70% for the wild-type (Ser49) and mutated (Gly49) alleles, respectively. Significant differences were observed in the allele frequencies of the Ser49Gly marker between the self-defined black and non-black phenotype, and the African and non-African descendant genotype population samples. A significant difference was also observed between blacks and African-descendant individuals, with a lesser degree of genetic differentiation. The results presented in the present study suggest that the Ser49Gly marker has a distribution that is influenced by an ancestral component, due to the increased prevalence of the Gly49 polymorphism in the black and African descendant populations of the Rio de Janeiro state. This evidence, in combination with clinical studies, may contribute to a detailed analysis of the pattern of susceptibility to CVD involved in ß-ADR1 receptor mechanism failure.