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Cardiac AT 1 Receptor/β‐Arrestin Pathway is a Neonatal‐Specific Druggable Target for Pediatric Heart Failureβ
Author(s) -
Yamada Mitsuhiko,
Kawagishi Hiroyuki,
Kadota Shin,
Shiba Yuji,
Morimoto Sachio
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01960
Subject(s) - inotrope , medicine , endocrinology , heart failure , chronotropic , arrestin , contractility , receptor , heart rate , g protein coupled receptor , blood pressure
We recently found a novel neonatal‐specific inotropic signaling pathway in murine cardiac myocytes (CMs): strong, long‐lasting activation of L‐type Ca 2+ channels (LTCC) through AT 1 receptor (AT 1 R), β‐arrestin 2, and casein kinase 2α’. A peptidyl β‐arrestin‐biased AT 1 R agonist (BBA) activates β‐arrestin and inhibits G protein after binding to AT 1 R. Taking our recent above finding into account, its effect was re‐analyzed in neonatal mice and human induced pluripotent cell‐derived CMs (hiPSC‐CMs). BBA caused a significant long‐acting positive inotropic but not chronotropic effect in neonatal mice. BBA significantly increased plasma adrenaline (but not serum aldosterone) levels. However, its inotropic effect was mediated by the cardiac AT 1 R/β‐arrestin/LTCC pathway but not adrenaline. BBA significantly increased the peak twitch Ca 2+ transients in isolated mouse neonatal ventricular CMs (mNVCMs) as well as hiPSC‐CMs exhibiting fetal to neonatal phenotype. It moderately increased unloaded oxygen consumption of spontaneously beating mNVCMs by ~30% but not oxidative stress in the neonatal heart. BBA also significantly enhanced the contractility of the compromised heart of neonatal knock‐in mice bearing a point mutation causing human congenital DCM. Therefore, cardiac AT 1 receptor /β‐arrestin pathway is a neonatal‐specific druggable target for pediatric heart failure.