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alpha(1A)-adrenergic receptor-directed autoimmunity induces left ventricular damage and diastolic dysfunction in rats

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Item Type:Article
Title:alpha(1A)-adrenergic receptor-directed autoimmunity induces left ventricular damage and diastolic dysfunction in rats
Creators Name:Wenzel, K. and Wallukat, G. and Qadri, F. and Huebner, N. and Schulz, H. and Hummel, O. and Herse, F. and Heuser, A. and Fischer, R. and Heidecke, H. and Luft, F.C. and Mueller, D.N. and Dietz, R. and Dechend, R.
Abstract:BACKGROUND: Agonistic autoantibodies to the alpha(1)-adrenergic receptor occur in nearly half of patients with refractory hypertension; however, their relevance is uncertain. METHODS/PRINCIPAL FINDINGS: We immunized Lewis rats with the second extracellular-loop peptides of the human alpha(1A)-adrenergic receptor and maintained them for one year. alpha(1A)-adrenergic antibodies (alpha(1A)-AR-AB) were monitored with a neonatal cardiomyocyte contraction assay by ELISA, and by ERK1/2 phosphorylation in human alpha(1A)-adrenergic receptor transfected Chinese hamster ovary cells. The rats were followed with radiotelemetric blood pressure measurements and echocardiography. At 12 months, the left ventricles of immunized rats had greater wall thickness than control rats. The fractional shortening and dp/dt(max) demonstrated preserved systolic function. A decreased E/A ratio in immunized rats indicated a diastolic dysfunction. Invasive hemodynamics revealed increased left ventricular end-diastolic pressures and decreased dp/dt(min). Mean diameter of cardiomyocytes showed hypertrophy in immunized rats. Long-term blood pressure values and heart rates were not different. Genes encoding sarcomeric proteins, collagens, extracellular matrix proteins, calcium regulating proteins, and proteins of energy metabolism in immunized rat hearts were upregulated, compared to controls. Furthermore, fibrosis was present in immunized hearts, but not in control hearts. A subset of immunized and control rats was infused with angiotensin (Ang) II. The stressor raised blood pressure to a greater degree and led to more cardiac fibrosis in immunized, than in control rats. CONCLUSIONS/SIGNIFICANCE: We show that alpha(1A)-AR-AB cause diastolic dysfunction independent of hypertension, and can increase the sensitivity to Ang II. We suggest that alpha(1A)-AR-AB could contribute to cardiovascular endorgan damage.
Keywords:Amino Acid Sequence, Newborn Animals, Autoantibodies, Autoimmunity, Blood Pressure, CHO Cells, Diastole, Electrocardiography, Enzyme-Linked Immunosorbent Assay, Gene Expression Profiling, Heart, Immunoglobulin G, Molecular Sequence Data, Myocardium, Cardiac Myocytes, Adrenergic, alpha-1 Receptors, Reverse Transcriptase Polymerase Chain Reaction, Animals, Cricetinae, Cricetulus, Rats
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e9409
Date:24 February 2010
Official Publication:https://doi.org/10.1371/journal.pone.0009409
PubMed:View item in PubMed

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