Effectiveness and safety of a therapeutic vaccine against angiotensin II receptor type 1 in hypertensive animals.

Primary hypertension is a chronic disease with high morbidity, and the rate of controlled blood pressure is far from satisfactory, worldwide. Vaccination provides a promising approach for treatment of hypertension and improvement in compliance. Here, the ATRQ beta-001 vaccine, a peptide (ATR-001) derived from human angiotensin II (Ang II) receptor type 1 conjugated with Q beta bacteriophage virus-like particles, was developed and evaluated in animal models of hypertension. The ATRQ beta-001 vaccine significantly decreased the blood pressure of Ang II-induced hypertensive mice up to 35 mm Hg (143 +/- 4 versus 178 +/- 6 mm Hg; P=0.005) and that of spontaneously hypertensive rats up to 19 mm Hg (173 +/- 2 versus 192 +/- 3 mm Hg; P=0.003) and prevented remodeling of vulnerable hypertensive target organs. No obvious feedback activation of circulating or local renin-angiotensin system was observed. Additionally, no significant immune-mediated damage was detected in vaccinated hypertensive and nonhypertensive animals. The half-life of the anti-ATR-001 antibody was 14.4 days, surpassing that of existing chemical drugs. In vitro, the anti-ATR-001 antibody specifically bound to Ang II receptor type 1 and inhibited Ca2+-dependent signal transduction events, including protein kinase C-alpha translocation, extracellular signal- regulated kinase 1/2 phosphorylation (72% decrease; P=0.013), and elevation of intracellular Ca2+ (68% decrease; P=0.017) induced by Ang II, but without inhibiting Ang II binding to the receptor. In conclusion, the ATRQ beta-001 vaccine decreased the blood pressure of Ang II-induced hypertensive mice and spontaneously hypertensive rats effectively through diminishing the pressure response and inhibiting signal transduction initiated by Ang II. Thus, the ATRQ beta-001 vaccine may provide a novel and promising method for the treatment of primary hypertension. (Hypertension. 2013;61:408-416.) circle Online Data Supplement