title: Alpha1A-adrenergic receptor-directed autoimmunity induces left ventricular damage and diastolic dysfunction in rats.
abstract: BACKGROUND
  Agonistic autoantibodies to the alpha(1)-adrenergic receptor occur in nearly half of patients with refractory hypertension; however, their relevance is uncertain.
  
  
  RESULTS
  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
  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.
authors.affiliation: Medical Faculty of the Charité, Berlin, Germany. katrin.wenzel@charite.de
authors.forename: Katrin
authors.initials: K
authors.lastname: Wenzel
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.forename: Oliver
authors.initials: O
authors.lastname: Hummel
authors.forename: Florian
authors.initials: F
authors.lastname: Herse
authors.forename: Arnd
authors.initials: A
authors.lastname: Heuser
authors.forename: Robert
authors.initials: R
authors.lastname: Fischer
authors.forename: Harald
authors.initials: H
authors.lastname: Heidecke
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001323:Autoantibodies / Q000276:immunology / Q000494:pharmacology; D015551:Autoimmunity / Q000276:immunology*; D001794:Blood Pressure; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003971:Diastole; D004562:Electrocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D018340:Receptors, Adrenergic, alpha-1 / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D001323:Autoantibodies; D007074:Immunoglobulin G; D018340:Receptors, Adrenergic, alpha-1