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.
|
Authors | Annekathrin Haberland, Gerd Wallukat, Claudia Dahmen, Andreas Kage, Ingolf Schimke |
Journal | Circulation research
(Circ Res)
Vol. 109
Issue 9
Pg. 986-92
(Oct 14 2011)
ISSN: 1524-4571 [Electronic] United States |
PMID | 21868696
(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)
|