Abstract |
Angiotensin II (AngII) type I receptor (AT1R) recognizes AngII, a cardiovascular peptide hormone that acts as a terminal effector of the renin-angiotensin system (RAS). AT1R belongs to the rhodopsin-like peptidergic family of G protein-coupled receptors (GPCRs) and serves as a therapeutic target for the treatment of cardiovascular diseases, such as hypertension, cardiac hypertrophy and heart failure. Classically, AT1R was considered to signal only through G proteins. However, recent studies have revealed that AT1R is capable of activating G protein-independent signaling that is mediated by β- arrestins. β- arrestin is a cytosolic scaffold that is recruited to the activated GPCRs. In vitro and ex vivo studies have demonstrated that the activation of the AT1R-β-arrestin pathway stimulates contractility and exerts prosurvival effects in cardiomyocytes. TRV027, a potent synthetic β- arrestin-biased ligand for AT1R, specifically activates AT1R-β-arrestin signaling without stimulating G proteins. In preclinical studies, TRV027 not only produced vasodilation by antagonizing the AT1R-Gαq pathway but also enhanced cardiac performance by activating AT1R-β-arrestin signaling. Because of this unique pharmacological profile, TRV027 is now being evaluated in a phase II clinical trial as a novel therapeutic for acute heart failure (AHF).
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Authors | Yuichi Ikeda, Hidetoshi Kumagai, Yoshihiro Motozawa, Jun-Ichi Suzuki, Issei Komuro |
Journal | International heart journal
(Int Heart J)
Vol. 56
Issue 5
Pg. 485-8
( 2015)
ISSN: 1349-3299 [Electronic] Japan |
PMID | 26180022
(Publication Type: Journal Article, Review)
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Chemical References |
- Angiotensin II Type 1 Receptor Blockers
- Arrestins
- Oligopeptides
- Receptor, Angiotensin, Type 1
- beta-Arrestins
- Sar-Arg-Val-Tyr-Ile-His-Pro-Ala-OH
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Topics |
- Angiotensin II Type 1 Receptor Blockers
(pharmacology)
- Arrestins
(metabolism)
- Clinical Trials, Phase II as Topic
- Heart Failure
(drug therapy, metabolism, pathology)
- Humans
- Myocytes, Cardiac
(drug effects, metabolism)
- Oligopeptides
(pharmacology)
- Receptor, Angiotensin, Type 1
(metabolism)
- Renin-Angiotensin System
(drug effects)
- Signal Transduction
(drug effects)
- beta-Arrestins
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