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Potential relevance of alpha(1)-adrenergic receptor autoantibodies in refractory hypertension

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Item Type:Article
Title:Potential relevance of alpha(1)-adrenergic receptor autoantibodies in refractory hypertension
Creators Name:Wenzel, K. and Haase, H. and Wallukat, G. and Derer, W. and Bartel, S. and Homuth, V. and Herse, F. and Huebner, N. and Schulz, H. and Janczikowski, M. and Lindschau, C. and Schroeder, C. and Verlohren, S. and Morano, I. and Mueller, D.N. and Luft, F.C. and Dietz, R. and Dechend, R. and Karczewski, P.
Abstract:BACKGROUND: Agonistic autoantibodies directed at the alpha(1)-adrenergic receptor (alpha(1)-AAB) have been described in patients with hypertension. We implied earlier that alpha(1)-AAB might have a mechanistic role and could represent a therapeutic target. METHODOLOGY/PRINCIPAL FINDINGS: To pursue the issue, we performed clinical and basic studies. We observed that 41 of 81 patients with refractory hypertension had alpha(1)-AAB; after immunoadsorption blood pressure was significantly reduced in these patients. Rabbits were immunized to generate alpha(1)-adrenergic receptor antibodies (alpha(1)-AB). Patient alpha(1)-AAB and rabbit alpha(1)-AB were purified using affinity chromatography and characterized both by epitope mapping and surface plasmon resonance measurements. Neonatal rat cardiomyocytes, rat vascular smooth muscle cells (VSMC), and Chinese hamster ovary cells transfected with the human alpha(1A)-adrenergic receptor were incubated with patient alpha(1)-AAB and rabbit alpha(1)-AB and the activation of signal transduction pathways was investigated by Western blot, confocal laser scanning microscopy, and gene expression. We found that phospholipase A2 group IIA (PLA2-IIA) and L-type calcium channel (Cacna1c) genes were upregulated in cardiomyocytes and VSMC after stimulation with both purified antibodies. We showed that patient alpha(1)-AAB and rabbit alpha(1)-AB result in protein kinase C alpha activation and transient extracellular-related kinase (EKR1/2) phosphorylation. Finally, we showed that the antibodies exert acute effects on intracellular Ca(2+) in cardiomyocytes and induce mesentery artery segment contraction. CONCLUSIONS/SIGNIFICANCE: Patient alpha(1)-AAB and rabbit alpha(1)-AB can induce signaling pathways important for hypertension and cardiac remodeling. Our data provide evidence for a potential clinical relevance for alpha(1)-AAB in hypertensive patients, and the notion of immunity as a possible cause of hypertension.
Keywords:Adsorption, Autoantibodies, Blood Pressure, Calcium, L-Type Calcium Channels, Enzyme Activation, Epitope Mapping, Extracellular Signal-Regulated MAP Kinases, Hypertension, Intracellular Space, Vascular Smooth Muscle Cardiac Myocytes, Smooth Muscle Myocytes, Phospholipases A2, Protein Kinase C, Secondary Protein Structure, alpha Adrenergic Receptors, Animals, Rats
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e3742
Date:17 November 2008
Official Publication:https://doi.org/10.1371/journal.pone.0003742
PubMed:View item in PubMed

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