Vaccine Targeted Alpha 1D-Adrenergic Receptor for Hypertension

Abstract

The α1-AR (α1 adrenergic receptor) blockers currently on the market cannot meet clinical needs because of low-selectivity for subtypes of α1-ARs, short half-life, and uncertain role in cardiovascular end point events. The study sought to find a vaccine specifically against α1D-AR (α1D-adrenergic receptor) for treating hypertension. A short peptide ADR-004 (cgiteeagy) belonging to α1D-AR was screened, and the ADRQβ-004 vaccine was produced and injected into spontaneously hypertensive rats model (including a short-term study, 10 weeks, and a long-term observation study, 39 weeks) and NG-nitro-l-arginine methyl ester + spontaneously hypertensive rats model (15 weeks). The antihypertensive effect and target organ protection of the ADRQβ-004 vaccine were carefully evaluated. The possible immune-mediated damage was detected in normal vaccinated Sprague Dawley rats. The ADR-004 peptide has perfect immunogenicity, and the ADRQβ-004 vaccine could induce strong antibody production. In the short-term study, the ADRQβ-004 vaccine averagely decreased the systolic blood pressure of spontaneously hypertensive rats up to 15 mm Hg and that of NG-nitro-l-arginine methyl ester+spontaneously hypertensive rats up to 29 mm Hg. In the long-term observation model, the antihypertensive effect of the ADRQβ-004 vaccine was quite stable, and the average decline of systolic blood pressure was 22 mm Hg. The ADRQβ-004 vaccine effectively prevented vascular structural remodeling, cardiac hypertrophy and fibrosis, and renal injury of hypertensive animals, superior to prazosin at renal level. Moreover, the ADRQβ-004 vaccine obviously downregulated the expression of α1D-AR, but not α1A-AR. Additionally, no significant immune-mediated damage was detected in immunized animals. The present results demonstrate that the ADRQβ-004 vaccine may provide a novel and promising method for the treatment of hypertension.