Alpha1A-adrenergic receptor-directed autoimmunity induces left ventricular damage and diastolic dysfunction in rats.
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.
Wenzel
Katrin
K
Medical Faculty of the Charité, Berlin, Germany. katrin.wenzel@charite.de
Wallukat
Gerd
G
Qadri
Fatimunnisa
F
Hubner
Norbert
N
Schulz
Herbert
H
Hummel
Oliver
O
Herse
Florian
F
Heuser
Arnd
A
Fischer
Robert
R
Heidecke
Harald
H
Luft
Friedrich C
FC
Muller
Dominik N
DN
Dietz
Rainer
R
Dechend
Ralf
R
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
C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D001323:Autoantibodies; D007074:Immunoglobulin G; D018340:Receptors, Adrenergic, alpha-1