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


RESULTS
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
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.
Wenzel
Katrin
K
Medical Faculty of the Charité, Franz-Volhard Clinic and HELIOS Klinikum-Berlin, Experimental and Clinical Research Center, Berlin, Germany.
Haase
Hannelore
H
Wallukat
Gerd
G
Derer
Wolfgang
W
Bartel
Sabine
S
Homuth
Volker
V
Herse
Florian
F
Hubner
Norbert
N
Schulz
Herbert
H
Janczikowski
Marion
M
Lindschau
Carsten
C
Schroeder
Christoph
C
Verlohren
Stefan
S
Morano
Ingo
I
Muller
Dominik N
DN
Luft
Friedrich C
FC
Dietz
Rainer
R
Dechend
Ralf
R
Karczewski
Peter
P
D000327:Adsorption / Q000187:drug effects; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000302:isolation & purification / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018604:Epitope Mapping; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000276:immunology* / Q000503:physiopathology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D054467:Phospholipases A2 / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017433:Protein Structure, Secondary; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000737:chemistry / Q000276:immunology*
D001323:Autoantibodies; C504728:Cacna1c protein, rat; D020746:Calcium Channels, L-Type; D011942:Receptors, Adrenergic, alpha; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D054467:Phospholipases A2; D002118:Calcium