Biased agonism of the angiotensin II type I receptor a potential strategy for the treatment of acute heart failure

Yuichi Ikeda, Hidetoshi Kumagai, Yoshihiro Motozawa, Jun Ichi Suzuki, Issei Komuro

Research output: Contribution to journalArticle

15 Citations (Scopus)

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).

Original languageEnglish (US)
Pages (from-to)485-488
Number of pages4
JournalInternational Heart Journal
Volume56
Issue number5
DOIs
StatePublished - Sep 29 2015

Fingerprint

Arrestin
Angiotensin I
Angiotensin Receptors
Heart Failure
GTP-Binding Proteins
G-Protein-Coupled Receptors
Arrestins
Phase II Clinical Trials
Rhodopsin
Peptide Hormones
Cardiomegaly
Renin-Angiotensin System
Cardiac Myocytes
Vasodilation
Angiotensin II
Cardiovascular Diseases
Pharmacology
Ligands
Hypertension
Therapeutics

Keywords

  • GPCR
  • Novel cardiovascular therapeutic
  • TRV027
  • β-arrestin
  • β-arrestin-biased ligand

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Biased agonism of the angiotensin II type I receptor a potential strategy for the treatment of acute heart failure. / Ikeda, Yuichi; Kumagai, Hidetoshi; Motozawa, Yoshihiro; Suzuki, Jun Ichi; Komuro, Issei.

In: International Heart Journal, Vol. 56, No. 5, 29.09.2015, p. 485-488.

Research output: Contribution to journalArticle

Ikeda, Yuichi ; Kumagai, Hidetoshi ; Motozawa, Yoshihiro ; Suzuki, Jun Ichi ; Komuro, Issei. / Biased agonism of the angiotensin II type I receptor a potential strategy for the treatment of acute heart failure. In: International Heart Journal. 2015 ; Vol. 56, No. 5. pp. 485-488.
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