Cardiac AT 1 Receptor/β‐Arrestin Pathway is a Neonatal‐Specific Druggable Target for Pediatric Heart Failureβ

Abstract

We recently found a novel neonatal-specific inotropic signaling pathway in murine cardiac myocytes (CMs): strong, long-lasting activation of L-type Ca2+ channels (LTCC) through AT1 receptor (AT1R), β-arrestin 2, and casein kinase 2α’. A peptidyl β-arrestin-biased AT1R agonist (BBA) activates β-arrestin and inhibits G protein after binding to AT1R. 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 AT1R/β-arrestin/LTCC pathway but not adrenaline. BBA significantly increased the peak twitch Ca2+ 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 AT1 receptor /β-arrestin pathway is a neonatal-specific druggable target for pediatric heart failure.