Reduction of Blood Pressure by AT 1 Receptor Decoy Peptides

Background: We previously identified the binding of the chaperone protein gamma-aminobutyric acid receptor–associated protein (GABARAP) to a sequence on the carboxyterminus of the angiotensin II AT1 receptor (AT1R) and showed that this binding enhances AT1R trafficking to the cell surface as well as angiotensin signaling. Methods: In this study, we treated sodium-depleted mice with decoy peptides consisting either of a fusion of the cellpenetrating peptide penetratin and the GABARAP/AT1R binding sequence or penetratin fused to a mutated AT1R sequence. We used telemetry to measure blood pressure. Results: Systolic and diastolic pressure fell during the 24 hours following decoy peptide injection but not after control peptide injection. Active cell-penetrating decoy peptide decreased 24-hour average systolic blood pressure from 129.8 – 4.7 mmHg to 125.0 – 6.0 mmHg (mean – standard deviation). Diastolic blood pressure fell from 99.0 – 7.1 mmHg to 95.0 – 9.2 mmHg (n¼5). Administration of the control peptide raised systolic blood pressure from 128.7 – 1.3 mmHg to 131.7 – 2.9 mmHg and diastolic pressure from 93.9 – 4.5 mmHg to 95.9 – 4.2 mmHg (n¼5). The decreases in both systolic and diastolic blood pressure after active peptide administration were statistically significant compared to control peptide administration (P<0.05, two-tailed Wilcoxon rank-sum test). Conclusion: These results indicate the physiological and potentially therapeutic relevance of inhibitors of GABARAP/ AT1R binding.