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Morphology change in pancreatic islet. H&E staining of pancreatic islet on week 28 was measured by optical microscope. An irregular islet structure and decreased islet area were observed in the β1-AA group compared with vehicle. Scale bar of 100 times, 200 times, 400 times magnification = 20, 10, 5 μm, respectively
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Diabetes mellitus is a chronic metabolic disorder with a high morbidity and mortality, but its pathogenesis is not fully understood. An increasing amount of evidence indicates that an immune mechanism plays an important role in the pathogenesis of diabetes. We demonstrated previously that the long-term presence of autoantibodies against the second...
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Administration of antibodies to sclerostin (Scl-Ab) has been shown to increase bone mass, bone mineral density (BMD) and bone strength by increasing bone formation and decreasing bone resorption in both animal studies and human clinical trials. In these studies, the magnitude and rate of increase in bone formation markers is attenuated upon repeat...
Citations
... Generation and Characterization of b 1 -AA Monoclonal Antibody b 1 -AA monoclonal antibody were generated by hybridoma technology, as we previously described. 23 Two peptides corresponding to the sequence (amino acid residues 197-223) of the second extracellular loop of the human b 1 -AR ...
Background
Autoantibodies against the second extracellular loop of the β1‐adrenoceptor (β1‐AA) act similarly to agonist of β1‐adrenergic receptor, which plays an important role in the pathophysiological characteristics of ventricular remodeling. Recently, considerable lines of evidence have suggested that CTRP9 (C1q tumor necrosis factor–related protein 9) is a potent cardioprotective cardiokine and protects the heart from ventricular remodeling. The aim of this study was to determine the role of CTRP9 in ventricular remodeling induced by β1‐AA.
Methods and Results
Blood samples were collected from 131 patients with coronary heart disease and 131 healthy subjects. The serum levels of β1‐AA and CTRP9 were detected using ELISA. The results revealed that CTRP9 levels in β1‐AA–positive patients were lower than those in β1‐AA–negative patients, and serum CTRP9 concentrations were inversely correlated with β1‐AA. β1‐AA monoclonal antibodies (β1‐AAmAbs) were administered in mice with and without rAAV9‐cTnT‐Full Ctrp9‐FLAG virus for 8 weeks. Reverse transcription–polymerase chain reaction/Western analysis showed that cardiomyocyte CTRP9 expression was significantly reduced in β1‐AAmAb–treated mice. Moreover, compared with the β1‐AAmAb alone group, cardiac‐specific CTRP9 overexpression improved cardiac function, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. Mechanistic studies demonstrated that CTRP9 overexpression decreased the levels of G‐protein–coupled receptor kinase 2 and promoted the activation of AMP‐dependent kinase pathway. However, cardiac‐specific overexpression of CTRP9 had no effect on the levels of cAMP and protein kinase A activity elevated by β1‐AAmAb.
Conclusions
This study provides the first evidence that the long‐term existence of β1‐AAmAb suppresses cardiac CTRP9 expression and exaggerates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathologic remodeling in β1‐AA–positive patients with coronary heart disease.
... So the inhibition of the renin-angiotensin system prevents T2D and decrease the incidence of new-onset diabetes (Jandeleit- Dahm et al., 2005). concerning ghrelin function in diabetes, findings showed that not only low plasma ghrelin is associated with insulin resistance and T2D prevalence but also this hormone stimulates insulin secretion from pancreas of either normal or diabetic rats (Adeghate and Ponery, 2002) also blood glucose increase was induced by autoantibodies against the β 1 -aderenegic receptor (Gong et al., 2016). Hence, the purpose of present study is that the most important genetic variant of ADRB-1 polymorphism (Arg389Gly) may effect on the T2D pathogenesis in a sample of Iranian population. ...
β1-Adrenegic receptor (ADRB-1) leads to increase both renin and ghrelin secretions which are considered to be two hormones associated with type 2 diabetes mellitus (T2D) and insulin resistance. So, to clarify the possible impact of ADRB-1 variant in T2D, we investigated rs1801253C/G (Arg38Gly) polymorphism in a sample of Iranian population. This case-control study was carried out in 500 unrelated Iranian subjects that used Tetra amplification refractory mutation system polymerase chain reaction (Tetra ARMS-PCR) for genotyping rs1801253C/G variant. The finding demonstrated a strong association between rs1801253C/G polymorphism and T2D in versus inherited models (GG vs. CC, OR = 2.88, CI = 1.44–5.78, p = 0.003; G vs. C OR = 1.87, CI = 1.31–2.67, p = 0.0006; CG + GG vs. CC OR = 1.64 CI = 1.06–2.500 p = 0.024; and GG vs. CC + CG OR = 2.78, CI = 1.41–5.56, p = 0.0021). Our findings suggest that ADRB-1 rs1801253C/G polymorphism was prominently associated with T2D in Iranian subjects. These remarkable results needed to evaluate in other investigations with larger sample sizes and different ethnicities to confirm.
... Chrysin has an important role on interleukin production, i.e. it has been established that, in pro-inflammatory conditions derived from LPS stimulation or ischemic/reperfusion events, the levels of IL-1α, IL-1β, IL-6, IL-8 and IL-12 are diminished [8]. These data prompted us to use athymic mice as a model to study the antidiabetic and anti-inflammatory activities of chrysin [9]. ...
... Chrysin has an important role on interleukin production, i.e. it has been established that, in pro-inflammatory conditions derived from LPS stimulation or ischemic/reperfusion events, the levels of IL-1α, IL-1β , IL-6, IL-8 and IL-12 are diminished [8]. These data prompted us to use athymic mice as a model to study the antidiabetic and anti-inflammatory activities of chrysin [9]. ...
Extensive knowledge of diabetes and its complications is helpful to find new drugs for proper treatment to stop degenerative changes derived from this disease. In this context, chrysin (5,7-dihydroxyflavone) is a natural product that occurs in a variety of flowers and fruits with anti-inflammatory and antidiabetic effects, among others. Thus, a diabetic model in athymic nude mice was developed and used to establish the ability of chrysin to decrease the secretion of pro-inflammatory cytokines. Also, it was determined the acute (50 mg/kg) and sub-acute (50 mg/kg/day/10 days) antidiabetic and antihyperlipidemic activities after the period of time treatment. Results indicate that chrysin has significant acute antihyperglycemic and antidiabetic effects in nude diabetic mice (p < 0.05). Moreover, triglyceride blood levels were reduced and IL-1β and TNF-α were diminished after 10 days’ treatment compared with control group (p < 0.05). In conclusion, it was found that chrysin could produce similar effects as metformin, a drug used for the treatment of diabetes, since both test samples decreased glucose and triglycerides levels, they impaired the generation of pro-inflammatory cytokines involved in the development of diabetes and its consequences, such as atherosclerosis and other cardiovascular diseases.
... Innate and adaptive immune cells also express βARs; these receptors have a major role in the interaction between the nervous and the immune systems [40][41][42] . Autoantibodies targeting β1AR from patients with dilated cardiomyopathy induce T cell proliferation via activation of signalling molecules such as cAMP and PKA 43 . ...
G protein-coupled receptors (GPCRs) comprise the largest and most diverse family of integral membrane proteins that participate in different physiological processes such as the regulation of the nervous and immune systems. Besides the endogenous ligands of GPCRs, functional autoantibodies are also able to bind GPCRs to trigger or block intracellular signalling pathways, resulting in agonistic or antagonistic effects, respectively. In this Review, the effects of functional GPCR-targeting autoantibodies on the pathogenesis of autoimmune diseases, including rheumatic diseases, are discussed. Autoantibodies targeting β1 and β2 adrenergic receptors, which are expressed by cardiac and airway smooth muscle cells, respectively, have an important role in the development of asthma and cardiovascular diseases. In addition, high levels of autoantibodies against the muscarinic acetylcholine receptor M3 as well as those targeting endothelin receptor type A and type 1 angiotensin II receptor have several implications in the pathogenesis of rheumatic diseases such as Sjögren syndrome and systemic sclerosis. Expanding the knowledge of the pathophysiological roles of autoantibodies against GPCRs will shed light on the biology of these receptors and open avenues for new therapeutic approaches.
... Innate and adaptive immune cells also express βARs; these receptors have a major role in the interaction between the nervous and the immune systems [40][41][42] . Autoantibodies targeting β1AR from patients with dilated cardiomyopathy induce T cell proliferation via activation of signalling molecules such as cAMP and PKA 43 . ...
Systemic sclerosis (SSc) is a complex and heterogeneous systemic autoimmune disease characterized by the presence of high serum levels of antibodies targeting a variety of self-antigens. In addition to autoantibodies directed against nuclear antigens, patients with SSc also develop high serum levels of functional autoantibodies that target cell surface receptors when compared to healthy subjects. Following binding to extracellular receptors, these functional autoantibodies trigger the activation of signal transducing pathways, resulting in a stimulatory or suppressive effect. For example, stimulatory autoantibodies toward platelet-derived growth factor receptor (PDGFR) or antibodies targeting G protein–coupled receptors (e.g., angiotensin II receptor type 1 and endothelin receptor type A) have pleiotropic roles in the pathogenesis of SSc. High levels of these functional autoantibodies dysregulate the response of non-immune cells (e.g., fibroblasts and endothelial cells) as well as innate and adaptive immune cells, including myeloid cells and lymphocytes, respectively. Thus, the immunobiology of such autoantibodies clarifies why patients with SSc develop clinical features such as extensive fibrosis, vasculopathies and abnormal immune responses. Future interventions that modulate the natural production of functional autoantibodies that target cell surface receptors or neutralize such autoantibodies would be essential in reducing morbidity and mortality rates presented by SSc patients.
Background:
Autoimmune disorder is the emerging mechanism of atrial fibrillation (AF).The β1-adrenergic receptor antibody (β1-AAb) is associated with AF progress. Our study aims to investigate whether β1-AAbs involves in atrial vulnerable substrate by mediating Ca2+ mishandling and atrial fibrosis in autoimmune associated AF.
Methods:
Active immunization models were established via subcutaneous injection of the second extracellular loop (ECL2) peptide for β1 adrenergic receptor (β1AR). Invasive electrophysiologic study and ex vivo optical mapping were used to evaluate the changed electrophysiology parameters and calcium handling properties. Phospho-proteomics combined with molecular biology assay were performed to identify the potential mechanisms of remodeled atrial substrate elicited by β1-AAbs. Exogenous β1-AAbs were used to induce the cellular phenotypes of HL-1 cells and atrial fibroblasts to AF propensity.
Results:
β1-AAbs aggravated the atrial electrical instability and atrial fibrosis. Bisoprolol alleviated the alterations of action potential duration (APD), Ca2+ transient duration (CaD) and conduction heterogeneity challenged by β1-AAbs. β1-AAbs prolonged calcium transient refractoriness and promoted arrhythmogenic atrial alternans and spatially discordant alternans, which were partly counteracted through blocking β1AR. Its underlying mechanisms are related to β1AR-drived CaMKII/RyR2 activation of atrial cardiomyocytes and the myofibroblasts phenotype formation of fibroblasts.
Conclusion:
Suppressing β1-AAbs effectively protects the atrial vulnerable substrate by ameliorating intracellular Ca2+ mishandling and atrial fibrosis, preventing the process of the autoimmune associated AF.
Cardiac dysfunction is involved in disorders of energy metabolism. High‐titer autoantibodies against the β1‐adrenoceptor (β1‐AAs) have been reported to exist in patients with cardiac dysfunction; however, the mechanism by which β1‐AAs affect cardiac function is unknown. This study aimed to determine whether β1‐AAs disturb myocardium energy metabolism and cause cardiac dysfunction. β1‐AA monoclonal antibodies (β1‐AAmAbs) were successfully pre‐synthesized by hybridoma clones and used in all experiments. β1‐AAmAbs impaired cardiac function and induced a myocardial metabolic disturbance, as evidenced by decreased left ventricular ejection fraction and fractional shortening. In addition, β1‐AAmAbs decreased the adenosine triphosphate level and increased cardiac energy consumption (Rate‐Pressure‐Product). We further showed that the effects of β1‐AAmAbs on heart tissue might involve the mitochondria and metabolic pathways via the β1‐adrenoceptor baased on an immunoprecipitation and mass spectrometry. Additionally, we found that β1‐AAmAbs impaired myocardial mitochondrial structure, decreased the membrane potential, and induced insufficient mitophagy. In conclusion, β1‐AAmAb‐induced cardiac dysfunction is partly due to a disturbance in myocardial energy metabolism.
New Findings
What is the central question of this study?
High titres of autoantibodies against the second extracellular loop of the β 1 ‐adrenergic receptor (β 1 ‐AAs) can be detected in the sera of patients with ventricular arrhythmias, but a causal relationship between β 1 ‐AAs and ventricular arrhythmias has not been established.
What is the main finding and its importance?
Monoclonal β 1 ‐AAs (β 1 ‐AR mAbs) were used in the experiments. We showed that β 1 ‐AR mAbs increased susceptibility to ventricular arrhythmias and induced repolarization abnormalities. Antibody adsorption of β 1 ‐AAs will be a potential new therapeutic strategy for ventricular arrhythmias in patients with high titres of β 1 ‐AAs.
High titres of autoantibodies against the second extracellular loop of the β 1 ‐adrenergic receptor (β 1 ‐AAs) can be detected in sera from patients with ventricular arrhythmias, but a causal relationship between β 1 ‐AAs and ventricular arrhythmias has not been established. In this work, ECGs of guinea‐pigs and isolated guinea‐pig hearts were recorded. Ventricular tachycardia (VT) and ventricular fibrillation (VF) were evoked by programmed electrical stimulation of the left ventricular epicardium of isolated guinea‐pig hearts. The monophasic action potential and effective refractory period of the left ventricle were recorded in paced isolated guinea‐pig hearts. Furthermore, to increase the specificity, monoclonal autoantibodies against the second extracellular loop of the β 1 ‐adrenergic receptor (β 1 ‐AR mAbs) were used in all experiments. The results showed that β 1 ‐AR mAbs induced premature ventricular contractions in guinea‐pigs and isolated guinea‐pig hearts. In addition, β 1 ‐AR mAbs decreased the threshold of VT/VF and prolonged the duration of VT/VF. Furthermore, β 1 ‐AR mAbs shortened the corrected QT interval and effective refractory period, and prolonged late‐phase repolarization of the monophasic action potential (MAPD 90−30 ). These changes in electrophysiological parameters might be attributed, at least in part, to the arrhythmogenicity of β 1 ‐AR mAbs.
