BACKGROUND: We previously identified the binding of the chaperone protein gamma-aminobutyric acid receptor-associated protein (GABARAP) to a sequence on the carboxy-terminus 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 cell-penetrating 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 (n=5). 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 (n=5). 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.
BACKGROUND: We previously identified the binding of the chaperone protein gamma-aminobutyric acid receptor-associated protein (GABARAP) to a sequence on the carboxy-terminus 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 cell-penetrating 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 (n=5). 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 (n=5). 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.
Entities:
Keywords:
Angiotensin type 1 receptor; angiotensins; cell-penetrating peptides
Authors: Deng-Fu Guo; Isabelle Chenier; Julie L Lavoie; John S D Chan; Pavel Hamet; Johanne Tremblay; Xiang Mei Chen; Donna H Wang; Tadashi Inagami Journal: Hypertension Date: 2006-06-26 Impact factor: 10.190