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Aptamer neutralization of beta1-adrenoceptor autoantibodies isolated from patients with cardiomyopathies

Item Type:Article
Title:Aptamer neutralization of beta1-adrenoceptor autoantibodies isolated from patients with cardiomyopathies
Creators Name:Haberland, A. and Wallukat, G. and Dahmen, C. and Kage, A. and Schimke, I.
Abstract:Rationale: Autoantibodies directed against the beta1-adrenoceptor (beta1-AABs) have been proposed to drive the pathogenesis of idiopathic dilated cardiomyoparthy (DCM), Chagas' cardiomyopathy, and peripartum cardiomyopathy. For disease treatment, aptamers that bind and neutralize beta1-AABs could be significant. Objective: We determined whether oligonucleotide-aptamers, selected to target human beta1-AABs directed against the second extracellular loop of the beta1-AAB, can neutralize these AABs and modulate their function in vitro. Methods and Results: Using Monolex technology, we identified an ssDNA aptamer that targets human beta1-AABs. The neutralization potential of this aptamer against beta1-AABs isolated from patients with DCM, Chagas' cardiomyopathy, and peripartum cardiomyopathy was analyzed using cultured neonatal rat cardiomyocytes by monitoring beta1-AAB induced cell toxicity and chronotropic cell responses.Aptamer addition reduced beta1-AAB induced cell toxicity and neutralized chonotropic beta1-AAB function in a dose-dependent manner. In the presence of aptamer neutralized beta1-AABs, cells remained fully responsive to agonists and antagonists, such as isoprenaline and bisoprolol. Both aptamer pretreated with a complementary (antisense) aptamer and a control scrambled-sequence aptamer were ineffective at beta1-AAB neutralization. Beta1-AABs directed against the first extracellular loop of the beta1-receptor and AABs directed against other G-protein coupled receptors were not affected by the selected aptamer. Conclusions: A specific aptamer that can neutralize cardiomyopathy associated human beta1-AABs in vitro has been identified and characterized, providing a framework for future in vivo testing of this treatment option in animal experiments.
Keywords:Aptamer, Autoantibodies, beta1-Adrenoceptor, Cardiomyopathy, Heart Failure, Adrenergic beta-1 Receptor Agonists, Antibody Specificity, Apoptosis, Nucleotide Aptamers, Bisoprolol, Dilated Cardiomyopathy, Cultured Cells, Chagas Cardiomyopathy, Drug Dose-Response Relationship, Isoproterenol, Cardiac Myocytes, Adrenergic beta-1 Receptors, Animals, Rats
Source:Circulation Research
Publisher:American Heart Association (U.S.A.)
Page Range:986-992
Date:14 October 2011
Official Publication:https://doi.org/10.1161/CIRCRESAHA.111.253849
PubMed:View item in PubMed

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