共查询到7条相似文献,搜索用时 15 毫秒
1.
Beta adrenergic receptor (β-AR) subtypes act through diverse signaling cascades to modulate cardiac function and remodeling. Previous in vitro studies suggest that β1-AR signaling is cardiotoxic whereas β2-AR signaling is cardioprotective, and may be the case during ischemia/reperfusion in vivo. The objective of this study was to assess whether β2-ARs also play a cardioprotective role in the pathogenesis of non-ischemic forms of cardiomyopathy. To dissect the role of β1 vs β2-ARs in modulating MLP (Muscle LIM Protein) cardiomyopathy, we crossbred MLP −/− with β1 −/− or β2 −/− mice. Deletion of the β2-AR improved survival, cardiac function, exercise capacity and myocyte shortening; by contrast haploinsufficency of the β1-AR reduced survival. Pathologic changes in Ca2 + handling were reversed in the absence of β2-ARs: peak Ca2 + and SR Ca2 + were decreased in MLP −/− and β1 +/−/MLP −/− but restored in β2 −/− MLP −/−. These changes were associated with reversal of alterations in troponin I and phospholamban phosphorylation. Gi inhibition increased peak and baseline Ca2 +, recapitulating changes observed in the β2 −/−/MLP −/−. The L-type Ca2 + blocker verapamil significantly decreased cardiac function in β2 −/− MLP −/− vs WT. We next tested if the protective effects of β2-AR ablation were unique to the MLP model using TAC-induced heart failure. Similar to MLP, β2 −/− mice demonstrated delayed progression of heart failure with restoration of myocyte shortening and peak Ca2 + and Ca2 + release. Deletion of β2-ARs prevents the development of MLP −/− cardiomyopathy via positive modulation of Ca2 + due to removal of inhibitory Gi signaling and increased phosphorylation of troponin I and phospholamban. Similar effects were seen after TAC. Unlike previous models where β2-ARs were found to be cardioprotective, in these two models, β2-AR signaling appears to be deleterious, potentially through negative regulation of Ca2 + dynamics. 相似文献
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Gadi Peleg Pejman Ghanouni Brian K. Kobilka Richard N. Zare 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(15):8469-8474
Single-molecule studies of the conformations of the intact beta(2) adrenergic receptor were performed in solution. Photon bursts from the fluorescently tagged adrenergic receptor in a micelle were recorded. A photon-burst algorithm and a Poisson time filter were implemented to characterize single molecules diffusing across the probe volume of a confocal microscope. The effects of molecular diffusion and photon number fluctuations were deconvoluted by assuming that Poisson distributions characterize the molecular occupation and photon numbers. Photon-burst size histograms were constructed, from which the source intensity distributions were extracted. Different conformations of the beta(2) adrenergic receptor cause quenching of the bound fluorophore to different extents and hence produce different photon-burst sizes. An analysis of the photon-burst histograms shows that there are at least two distinct substates for the native adrenergic membrane receptor. This behavior is in contrast to one peak observed for the dye molecule, rhodamine 6G. We test the reliability and robustness of the substate number determination by investigating the application of different binning criteria. Conformational changes associated with agonist binding result in a marked change in the distribution of photon-burst sizes. These studies provide insight into the conformational heterogeneity of G protein-coupled receptors in the presence and absence of a bound agonist. 相似文献
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Sato K Nakamura A Shirakawa J Muraoka T Togashi Y Shinoda K Orime K Kubota N Kadowaki T Terauchi Y 《Endocrinology》2012,153(3):1093-1102
Type 2 diabetes is characterized by diminished pancreatic β-cell mass and function. Glucagon-like peptide-1 has been reported to increase islet cell proliferation and reduce apoptosis of β-cells in rodents. In this study, we explored the effect of chronic administration of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance, β-cell function, and β-cell mass in Irs2-knockout (Irs2(-/-)) mice. Wild-type and Irs2(-/-) mice were fed a high-fat diet for 20 wk, with or without vildagliptin. In both genotypes of mice, vildagliptin significantly decreased the area under the curve (0-120 min) of blood glucose and increased the insulin response to glucose during the oral glucose tolerance test. In the oral glucose tolerance test performed 1 d after discontinuation of vildagliptin administration, the area under the curve (0-120 min) of blood glucose was still significantly decreased and the insulin response to glucose was significantly increased in the Irs2(-/-) mice treated with vildagliptin as compared with the values in the mice not treated with vildagliptin. Histochemical analysis of the pancreatic islets revealed significant increase of the β-cell mass and decrease in the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive β-cells but no significant increase of the bromodeoxyuridine incorporation in Irs2(-/-) mice treated with vildagliptin. Our results suggest that vildagliptin improved glucose tolerance and increased the β-cell mass by reducing β-cell apoptosis in the Irs2(-/-) mice, and that the reduction of β-cell apoptosis by vildagliptin was independent of the Irs2 expression in the cells. 相似文献
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Fu WP Zhao ZH Zhong L Sun C Fang LZ Liu L Zhang JQ Wang L Shu JK Wang XM Dai LM 《Respirology (Carlton, Vic.)》2011,16(8):1221-1227
Background and objective: Adrenergic β2 receptors (ADRB2) play an important role in regulating pulmonary function. Many previous studies have investigated possible associations between polymorphisms in the ADRB2 gene and asthma, but have yielded conflicting results. Furthermore, little is known regarding the possible role of the Arg19Cys polymorphism in susceptibility to asthma among Chinese. Methods: This case–control association study involved 238 patients with asthma and 265 healthy subjects from a Han population in southwest China. For all subjects, the 5′ leader cistron Arg19Cys, Arg16Gly and Gln27Glu polymorphisms in the ADRB2 gene were characterized by direct sequencing. Genotype, allele and haplotype frequencies were determined. In addition, to evaluate the association between the ADRB2 polymorphisms and lung function, bronchodilator response to inhaled β2 agonists (400 µg of albuterol) was assessed in the asthmatic patients. Results: There were no significant differences in genotype or allele frequencies for the three ADRB2 polymorphisms between the two cohorts. The Arg19/Arg16/Gln27 haplotype was more frequent among asthmatic patients than control subjects (odds ratio 2.24, 95% confidence interval (CI): 1.05–4.73, P = 0.04). Moreover, the Arg19/Cys19 genotype was associated with a lower FEV1% (mean difference ?4.5, 95% CI: ?12.5 to 3.6, P = 0.02) and FEV1/FVC (mean difference 8.9, 95% CI: 8.5–9.4, P = 0.01). The bronchodilator response to albuterol was also marginally lower in individuals who were homozygous for the Arg19 genotype (mean difference 4.2, 95% CI: 3.7–4.8, P = 0.03). Conclusions: The Arg19/Cys19 genotype was an independent risk factor for lower FEV1% and FEV1/FVC. Asthmatic patients with the Arg19/Arg19 genotype showed decreased responsiveness to albuterol. Furthermore, the Arg19/Arg16/Gln27 haplotype may contribute to increased susceptibility to asthma in the Chinese population. 相似文献
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In type 2 diabetes, although Akt/endothelial NO synthase (eNOS) activation is known to be negatively regulated by G protein-coupled receptor kinase 2 (GRK2), it is unclear whether the GRK2 inhibitor would have therapeutic effects. Here we examined the hypotensive effect of the GRK2 inhibitor and its efficacy agonist both vascular (aortic) endothelial dysfunction (focusing especially on the Akt/eNOS pathway) and glucose intolerance in two type 2 diabetic models (ob/ob mice and nicotinamide+streptozotocin-induced diabetic mice). Mice were treated with a single injection of the GRK2 inhibitor or vehicle, and the therapeutic effects were compared by examining vascular function and by Western blotting. The GRK2 inhibitor lowered blood pressure in both diabetic models but not in their age-matched controls. The GRK2 inhibitor significantly improved clonidine-induced relaxation only in diabetic (ob/ob and DM) mice, with accompanying attenuations of GRK2 activity and translocation to the plasma membrane. These protective effects of the GRK2 inhibitor may be attributable to the augmented Akt/eNOS pathway activation (as evidenced by increases in Akt phosphorylation at Ser(473) and at Thr(308), and eNOS phosphorylation at Ser(1177)) and to the prevention of the GRK2 translocation and promotion of β-arrestin 2 translocation to the membrane under clonidine stimulation. Moreover, the GRK2 inhibitor significantly improved the glucose intolerance seen in the ob/ob mice. Our work provides the first evidence that in diabetes, the GRK2 inhibitor ameliorates vascular endothelial dysfunction via the Akt/eNOS pathway by inhibiting GRK2 activity and enhancing β-arrestin 2 translocation under clonidine stimulation, thereby contributing to a blood pressure-lowering effect. We propose that the GRK2 inhibitor may be a promising therapeutic agent for cardiovascular complications in type 2 diabetes. 相似文献
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Neel Jayesh Shah Saka Vinod Kumar Umamaheswaran Gurusamy Arun Kumar Annan Sudarsan Deepak Gopal Shewade 《The Journal of asthma》2015,52(8):755-762
Introduction: Genetic mutations in the β2 receptor could alter its functioning and the response to β2 agonists. The study was done to find out the effect of two commonly occurring polymorphisms-Arg16Gly and Gln27Glu, on cause of asthma and on response to nebulized salbutamol in South Indian subjects of asthma. Methods: After baseline measurements of Forced Expiratory Volume in 1st second (FEV1), Forced Vital Capacity (FVC) and Peak Expiratory Flow Rate (PEFR), five mg of nebulized salbutamol was administered and spirometry was repeated. The increase in these parameters was calculated and patients were included for genotyping if the percentage increase in FEV1 was ≥12%. The frequencies of these polymorphisms in patients were compared with those of healthy volunteers. Results: 112 patients and 127 healthy volunteers were genotyped. The frequencies of the polymorphisms were found to be similar to previously published Dravidian population frequencies. The frequencies of genotypes in asthmatics were similar to healthy volunteers. The increase in FEV1, FVC and PEFR was similar across various genotypes and haplotypes in both the polymorphisms. The GG-CG haplotype was associated with 3.1 times increased occurrence of asthma (p value?=?0.02). The G allele of the Arg16Gly polymorphism was associated with lower baseline FEV1, FVC and PEFR values, but these were not statistically significant. Conclusion: The Arg16Gly and Gln27Glu polymorphisms do not determine the occurrence of asthma individually, but the GG-CG haplotype is associated with an increased risk of asthma. There is no effect of the genotypes on the response to nebulized salbutamol. 相似文献