DNA was extracted from the peripheral venous blood of 338 subjects using BLOOD DNA MINI KIT. The 5 site SNP in 3 subtypes of Beta-AR were genotyped by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) and allele-specific primer PCR techniques. The genotypes combination distribution of SNP at 5 sites in the 3 subtypes of Beta-AR were determined by clustering analysis technique. The natural combination distribution characteristics for SNP at 5 sites in the 3 subtypes of Beta-AR in 338 subjects were obtained. Sixty-seven combinations types were found. The preceding 5 combinations in the natural combination distribution of the SNP were: (1) The genotype combination of forty subjects was B1-AR S/S49+B1-AR R/R389+B2-AR R/G16+B2-AR Q/E27+B3-AR W/W64, its probability was 11.83%. (2) The genotype combination of thirty-three subjects was B1-AR S/S49+B1-AR R/R389+B2-AR R/G16+B2-AR Q/Q27+B3-AR W/W64, its probability was 9.76%. (3) The genotype combination of nineteen subjects was B1-AR S/S49+B1-AR R/G389+B2-AR R/G16+B2-AR Q/Q27+B3-AR W/W64, its probability was 5.62%. (4) The genotype combination of sixteen subjects was B1-AR S/S49+B1-AR R/G389+B2-AR R/G16+B2-AR Q/E27+B3-AR W/W64, its probability was 4.74%. (5) The genotype combination of thirteen subjects was B1-AR S/G49+B1-AR R/R389+B2-AR R/G16+B2-AR Q/E27+B3-AR W/W64, its probability was 3.85%. The obvious correlations exist among full sample and female or male subgroup, and between female and male subgroups.
Adult ; Aged ; Aged, 80 and over ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; methods ; Polymorphism, Single Nucleotide ; genetics ; Receptors, Adrenergic, beta ; classification ; genetics ; Receptors, Adrenergic, beta-1 ; genetics ; Receptors, Adrenergic, beta-2 ; genetics ; Receptors, Adrenergic, beta-3 ; genetics

OBJECTIVETo investigate the alteration of expressions of beta(1)-, beta(2)-, beta(3)-adrenoceptor mRNA in human myocardial tissue and the relation between their expressions and cardiac function in patient with heart failure.

METHODSThe mRNA expressions of beta(1)-, beta(2)- and beta(3)-adrenergic receptors in myocardial tissue were analyzed by using the reverse transcriptase-polymerase chain reaction in 24 patients with heart failure of valvular heart disease and 5 control subjects.

RESULTSBeta(1)-adrenergic receptor mRNA expressions in myocardium were significantly lower in patients with heart failure than those in control subjects, and progressively reduced with aggravation of heart function. By contrast, beta(3)-adrenoceptor mRNA expressions were significantly higher in patients with heart failure than those in controls, and progressively elevated with aggravation of cardiac function. No difference was observed in beta(2)-adrenergic receptor among all groups.

CONCLUSIONThe changes of beta-adrenergic receptor mRNA expression are associated with the severity of heart failure.

Adult ; Case-Control Studies ; Female ; Heart Failure ; genetics ; metabolism ; physiopathology ; Humans ; Male ; Middle Aged ; RNA, Messenger ; metabolism ; Receptors, Adrenergic, beta-1 ; genetics ; metabolism ; Receptors, Adrenergic, beta-2 ; genetics ; metabolism ; Receptors, Adrenergic, beta-3 ; genetics ; metabolism

In the heart, stimulation of beta-adrenergic receptors (betaAR) serves as the most powerful means to increase cardiac contractility and relaxation in response to stress or a "fight-or-flight" situation. However, sustained beta-adrenergic stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy, apoptosis and necrosis, thus contributing to the pathogenesis of chronic heart failure. Over the past decade, compelling evidence has demonstrated that coexisting cardiac betaAR subtypes, mainly beta(1)AR and beta (2)AR, activate markedly different signaling cascades. As a result, acute beta(1)AR stimulation activates the G(s) -adenylyl cyclase-cAMP-PKA signaling that can broadcast throughout the cell, whereas beta(2)AR-evoked cAMP signaling is spatially and functionally compartmentalized, due to concurrent G(i) activation. Chronic stimulation of beta(1)AR and beta(2)AR elicits opposing effects on the fate of cardiomyocytes: beta(1)AR induces hypertrophy and apoptosis; but beta(2)AR promotes cell survival. The cardiac protective effect of beta(2)AR is mediated by a signaling pathway sequentially involving G(i), G(betagamma), PI3K and Akt. Unexpectedly, beta(1)AR-induced myocyte hypertrophy and apoptosis are independent of the classic cAMP/PKA pathway, but require activation of Ca(2+)/calmodulin-dependent kinase II (CaMK II). The outcomes of cardiac-specific transgenic overexpression of either beta AR subtype in mice have reinforced the fundamentally different functional roles of these betaAR subtypes in governing cardiac remodeling and performance. These new insights regarding betaAR subtype stimulation not only provide clues as to cellular and molecular mechanisms underlying the beneficial effects of beta AR blockers in patients with chronic heart failure, but also delineate rationale for combining selective beta(1)AR blockade with moderate beta(2)AR activation as a potential novel therapy for the treatment of chronic heart failure.
Adenylyl Cyclases ; metabolism ; Animals ; Cyclic AMP-Dependent Protein Kinases ; metabolism ; GTP-Binding Proteins ; metabolism ; Heart ; physiology ; Heart Failure ; physiopathology ; Humans ; Myocardium ; metabolism ; Receptors, Adrenergic, beta ; classification ; physiology ; Receptors, Adrenergic, beta-1 ; physiology ; Receptors, Adrenergic, beta-2 ; physiology ; Signal Transduction

OBJECTIVETo determine whether autoantibodies against the cardiac G-protein-coupled beta 2- and alpha 1-adrenergic and AT1 receptors are related to patients with primary hypertension.

METHODSSynthetic peptides corresponding to amino acid sequences of the second extracellular loops of the beta 2- and alpha 1-adrenergic and AT1 receptors were respectively used as antigens to screen sera from patients with hypertensive heart diseases (n = 50) as well as simple hypertension (n = 40) and healthy blood donors (n = 40) using ELISA test.

RESULTSThe positive ratio of autoantibodies against beta 2 and alpha 1 and AT1 receptors in patients with hypertensive heart diseases were significantly higher than patients with simple hypertension and healthy donors. The geometric mean titers of autoantibodies against beta 2- and alpha 1-adrenergic and AT1 receptors had no difference between the patients with hypertensive heart diseases and the patients with simple hypertension, but the geometric mean titers of two groups were higher than healthy donors. In the patients with hypertensive heart diseases, 81.0% of the patients with autoantibodies against beta 2-adrenergic receptor had autoantibodies against alpha 1-adrenergic receptor and 76.2% had autoantibodies against AT1 receptors. The percent of the autoantibodies against three receptors in patients with hypertensive heart diseases were 52.4%.

CONCLUSIONSAutoantibodies against beta 2- and alpha 1-adrenergic and AT1 receptors play an important role in the pathophysiological changes of primary hypertension, and may participate myocardial and vessel remodeling.

Adult ; Aged ; Autoantibodies ; blood ; Female ; Humans ; Hypertension ; immunology ; Male ; Middle Aged ; Receptor, Angiotensin, Type 1 ; immunology ; Receptors, Adrenergic, alpha-1 ; immunology ; Receptors, Adrenergic, beta-2 ; immunology

BACKGROUND: The beta2 adrenergic receptor (beta2 AR) polymorphisms occurring at amino acid position 16 (Arg to Gly), 27 (Gln to Glu), 34 (Val to Met), and 164 (Thr to Ile) are known to be functionally relevant and also disease-modifying in subjects with asthma. However the contribution of these polymorphisms to the development of the asthmatic phenotype or other markers for allergic disease remains to be established. METHODS: 109 patients with bronchial asthma and 42 healthy person were included. Serum total IgE, allergen specific IgE, and skin prick test were performed to all of the subjects. beta2 AR polymorphisms were checked by mutated allele specific amplification (MASA) method. RESULTS: The results were as follows. The frequencies of beta2 AR polymorphisms in asthmatic patients and healthy person were not statistically different(p>0.05). There was no association between beta2 AR polymorphisms of amino acid position 16, 27, 34 and the existence of atopy among asthmatic patients (p>0.05). Between asthmatic patients with or without elevated IgE level and beta2 AR polymorphisms of amino acid position 16, 27, 34, there was no statistically significant association(p>0.05). CONCLUSION: There was no difference in frequency of the beta2 AR polymorphism between asthmatic patients and healthy person. In the bronchial asthma, association of beta2 AR polymorphism and atopy/serum total IgE was not found.
Alleles ; Asthma ; Humans ; Immunoglobulin E* ; Phenotype ; Receptors, Adrenergic ; Receptors, Adrenergic, beta-2 ; Skin

BACKGROUND AND PURPOSE: The purpose of this meta-analysis was to determine the precise association between beta-2 adrenergic receptor (beta2AR) polymorphism and Ischemic stroke. METHODS: Published case control studies on association between beta2AR and ischemic stroke were searched from electronic databases. Pooled Odds ratio and 95% Confidence interval were calculated by using software RevMan version 5.2. RESULTS: A total of three studies involving 1,642 cases and 1,673 controls, which were published from 2007 to 2014, were subjected to meta-analysis for allelic association and 518 cases and 510 controls for genotypic association. Pooled analysis of two studies for genotypic association suggested that subjects carrying Gln27Glu polymorphism of beta2AR had an increased risk for Ischemic stroke under recessive model (OR 2.09; 95% CI; 1.20 to 3.64) and under dominant model (OR 1.47; 95% CI 1.14 to 1.90). Pooled analysis of three studies for allelic association showed a significantly higher Glu27 allele of beta2AR in the patients with ischemic stroke (OR 1.58; 95% CI; 1.38 to 1.81). CONCLUSIONS: The present meta-analysis suggests that Gln27Glu polymorphism of beta2AR gene is associated with increased risk for ischemic stroke.
Alleles ; Case-Control Studies ; Cerebral Infarction ; Humans ; Odds Ratio ; Receptors, Adrenergic* ; Receptors, Adrenergic, beta-2 ; Stroke*

BACKGROUNDImbalance of the sympathetic nervous system was involved in the pathogenesis of idiopathic ventricular outflow-tract tachycardia (IVOT). We aimed to investigate whether the major genetic variants in β(1)- and β(2)-adrenoceptors and GNB3 C825T were associated with IVOT and verapamil sensitive idiopathic left ventricular tachycardia (ILVT).

METHODSPatients with IVOT and ILVT from December 2005 to December 2007 were consecutively enrolled into this study. Controls were randomly selected from the community-based inhabitants. Five genetic variants, Ser49Gly and Gly389Arg in the β(1)-adrenoceptor, Arg16Gly and Gln27Glu in the β(2)-adrenoceptor and GNB3 C825T, were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis.

RESULTSA total of 227 patients with IVOT and 110 patients with ILVT were included. Genotyping revealed that the 16Gly allele of Arg16Gly variant of β(2)-adrenoceptor was associated with a higher risk of IVOT (OR: 1.40, 95%CI: 1.12 - 1.75, P = 0.003 in the addictive model and OR: 1.62, 95%CI: 1.14 - 2.31, P = 0.007 in the dominant model). Patients with Gly16Gln27 haplotype also had a higher risk of IVOT (OR: 1.38, 95%CI: 1.11 - 1.73, P = 0.012). Other four variants, including Ser49Gly and Arg389Gly in β(1)-adrenoceptor, Gln27Glu in β(2)-adrenoceptor and GNB3 C825T, did not differ between patients with IVOT and controls. In patients with ILVT, no significant difference was found in these five variants compared with controls.

CONCLUSIONSArg16Gly in β(2)-adrenoceptor is significantly associated with IVOT in Chinese Han population. Major genetic variants in β(1)- and β(2)-adrenoceptor and GNB3 C825T may not be associated with ILVT. These data suggest a different arrhythmogenic mechanism in IVOT and ILVT.

Adult ; Genetic Predisposition to Disease ; Genetic Variation ; Genotype ; Haplotypes ; Humans ; Male ; Middle Aged ; Receptors, Adrenergic, beta-1 ; genetics ; Receptors, Adrenergic, beta-2 ; genetics ; Sex Characteristics ; Tachycardia, Ventricular ; genetics ; Ventricular Function

OBJECTIVETo elucidate the relationship between rat hepatic stellate cells (HSC) and sympathetic neurotransmitter norepinephrine (NE) during liver fibrosis.

METHODSUsing immunofluorescence and RT-PCR, the expressions of a1 and b2-adrenoceptors in activated HSC were detected. Methyl thiazolyl tetrazolium (MTT) was adopted to investigate the effect of NE on the proliferation of HSC. Meanwhile, the expressions of collagen-1, transforming growth factor beta (TGFb) and smooth muscle a-actin (a-SMA) in NE-stimulated HSC were detected by RT-PCR. The contents of NE in HSC were determined by high performance liquid chromatography-electrochemical detector (HPLC-ECD).

RESULTSThe a1 and b2-adrenoceptors were expressed in HSC. NE markedly stimulated the proliferation of HSC in a concentration-dependent manner (F = 140.464, P less than 0.05). NE induced the mRNA expressions of collagen-1, TGFb and a-SMA in HSC (t= -4.160; t= -8.763; t= -17.651, P less than 0.05). HSC were synthesizing and releasing NE, especially when stimulated with platelet-derived growth factor (PDGF) (10 ng/ml) (t= -32.907, P less than 0.05).

CONCLUSIONOur findings show that HSC are direct targets of NE and HSC are hepatic neuroglial cells that produce and respond to sympathetic neurotransmitter norepinephrine, suggesting that interrupting sympathetic nervous system signaling may be useful in the treatment of liver fibrosis.

Actins ; metabolism ; Animals ; Cell Proliferation ; drug effects ; Cells, Cultured ; Collagen Type I ; metabolism ; Hepatic Stellate Cells ; drug effects ; metabolism ; Liver Cirrhosis ; Norepinephrine ; pharmacology ; Rats ; Receptors, Adrenergic, alpha-1 ; metabolism ; Receptors, Adrenergic, beta-2 ; metabolism ; Transforming Growth Factor beta ; metabolism

A large number of β-adrenergic receptor (β-AR) agonists and antagonists are widely used in the treatment of cardiovascular diseases and other diseases. Nonetheless, it remains unclear whether these commonly used β-AR drugs can activate downstream β- arrestin-biased signaling pathways. The objective of this study was to investigate β-arrestin2 recruitment effects of β-AR agonists and antagonists that were commonly used in clinical practice. We used TANGO (transcriptional activation following arrestin translocation) assay to detect the β-arrestin2 recruitment by β-AR ligands in HEK293 cell line (HTLA cells) stably transfected with tetracycline transactivator protein (tTA) dependent luciferase reporter and β-arrestin2-TEV fusion gene. Upon activation of β-AR by a β-AR ligand, β-arrestin2 was recruited to the C terminus of the receptor, followed by cleavage of the G protein-coupled receptors (GPCRs) fusion protein at the TEV protease-cleavage site. The cleavage resulted in the release of tTA, which, after being transported to the nucleus, activated transcription of the luciferase reporter gene. The results showed that β-AR non-selective agonists epinephrine, noradrenaline and isoprenaline all promoted β-arrestin2 recruitment at β1-AR and β2-AR. β1-AR selective agonists dobutamine and denopamine both promoted β-arrestin2 recruitment at β1-AR. β2-AR selective agonists procaterol and salbutamol promoted β-arrestin2 recruitment at β2-AR. β-AR non-selective antagonists alprenolol and pindolol promoted β-arrestin2 recruitment at β1-AR. β1-AR selective antagonists celiprolol and bevantolol showed β-arrestin2 recruitment at β1-AR. β2-AR selective antagonists butoxamine showed β-arrestin2 recruitment at β1-AR. These results provide some clues for the potential action of β-AR drugs, and lay a foundation for the screening of β-arrestin-biased β-AR ligands.
Humans ; beta-Arrestin 2/metabolism* ; HEK293 Cells ; Adrenergic beta-Agonists/pharmacology* ; Isoproterenol/pharmacology* ; Receptors, Adrenergic, beta-2/metabolism* ; Norepinephrine/pharmacology*

BACKGROUNDSequence variants in the β-adrenergic receptor (ADRB) genes have a close relationship with the development of coronary artery disease (CAD) and the patient's prognosis. However, there is a lack of data on the role of the variants in ADRBs genes in Han Chinese patients with CAD. We aimed to investigate the association of genetic variants in the ADRB1 and ADRB2 genes with the incidence of major adverse cardiac event (MACE) in Han Chinese patients with CAD.

METHODSA total of 545 Han Chinese patients with CAD undergoing percutaneous coronary intervention (PCI) were recruited to the study and followed for one year. Three variant sites in ADRB1 (rs1801253) and ADRB2 (rs1042713 and rs1042714) were genotyped. The effect of the ADRB1 and ADRB2 genotypes on MACE within one year was assessed.

RESULTSThere were 47 cases of MACE during follow-up. There was no significant difference in the incidence of MACE among patients carrying different genotypes of the three variants in ADRB1 and ADRB2 (Log-rank, all P > 0.05). Cox regression analysis showed no association between three variants in ADRB1 and ADRB2 genes and the incidence of MACE during one-year follow-up, the adjusted hazard ratios (95% confidence interval) for rs1801253, rs1042713 and rs1042714 were 1.05 (0.54-2.02), 1.24 (0.58-2.64) and 1.66 (0.81-3.42), respectively.

CONCLUSIONOur data did not support a relationship between the three polymorphisms of ADRB1 (rs1801253) and ADRB2 (rs1042713 and rs1042714) genes and risk of subsequent cardiovascular events after PCI in Han Chinese patients with CAD.

Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group ; genetics ; Coronary Artery Disease ; genetics ; Female ; Genotype ; Humans ; Incidence ; Male ; Middle Aged ; Polymorphism, Genetic ; genetics ; Polymorphism, Single Nucleotide ; genetics ; Receptors, Adrenergic, beta ; genetics ; Receptors, Adrenergic, beta-1 ; genetics ; Receptors, Adrenergic, beta-2 ; genetics