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

AbstractRATIONALE:
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.
AuthorsAnnekathrin Haberland, Gerd Wallukat, Claudia Dahmen, Andreas Kage, Ingolf Schimke
JournalCirculation research (Circ Res) Vol. 109 Issue 9 Pg. 986-92 (Oct 14 2011) ISSN: 1524-4571 [Electronic] United States
PMID21868696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adrenergic beta-1 Receptor Agonists
  • Adrenergic beta-1 Receptor Antagonists
  • Aptamers, Nucleotide
  • Autoantibodies
  • Receptors, Adrenergic, beta-1
  • Isoproterenol
  • Bisoprolol
Topics
  • Adrenergic beta-1 Receptor Agonists (pharmacology)
  • Adrenergic beta-1 Receptor Antagonists (pharmacology)
  • Animals
  • Antibody Specificity
  • Apoptosis (drug effects, physiology)
  • Aptamers, Nucleotide (pharmacology)
  • Autoantibodies (drug effects, immunology, metabolism)
  • Bisoprolol (pharmacology)
  • Cardiomyopathy, Dilated (immunology)
  • Cells, Cultured
  • Chagas Cardiomyopathy (immunology)
  • Dose-Response Relationship, Drug
  • Humans
  • In Vitro Techniques
  • Isoproterenol (pharmacology)
  • Myocytes, Cardiac (drug effects, immunology, metabolism)
  • Rats
  • Receptors, Adrenergic, beta-1 (immunology, metabolism)

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