Potential Relevance of α(1)-Adrenergic Receptor Autoantibodies in Refractory Hypertension

BACKGROUND: Agonistic autoantibodies directed at the α(1)-adrenergic receptor (α(1)-AAB) have been described in patients with hypertension. We implied earlier that α(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 α(1)-AAB; after immunoadsorption blood pressure was significantly reduced in these patients. Rabbits were immunized to generate α(1)-adrenergic receptor antibodies (α(1)-AB). Patient α(1)-AAB and rabbit α(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 α(1A)-adrenergic receptor were incubated with patient α(1)-AAB and rabbit α(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 α(1)-AAB and rabbit α(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 α(1)-AAB and rabbit α(1)-AB can induce signaling pathways important for hypertension and cardiac remodeling. Our data provide evidence for a potential clinical relevance for α(1)-AAB in hypertensive patients, and the notion of immunity as a possible cause of hypertension.