β-Arrestin-Biased AT1 Agonist TRV027 Causes a Neonatal-Specific Sustained Positive Inotropic Effect Without Increasing Heart Rate

Toshihide Kashihara; Hiroyuki Kawagishi; Tsutomu Nakada; Takuro Numaga-Tomita; Shin Kadota; Elena E Wolf; Cheng-Kun Du; Yuji Shiba; Sachio Morimoto; Mitsuhiko Yamada

doi:10.1016/j.jacbts.2020.08.011

β-Arrestin-Biased AT₁ Agonist TRV027 Causes a Neonatal-Specific Sustained Positive Inotropic Effect Without Increasing Heart Rate

JACC Basic Transl Sci. 2020 Nov 11;5(11):1057-1069. doi: 10.1016/j.jacbts.2020.08.011. eCollection 2020 Nov.

Authors

Toshihide Kashihara¹, Hiroyuki Kawagishi^{1

2}, Tsutomu Nakada³, Takuro Numaga-Tomita¹, Shin Kadota^{2

4}, Elena E Wolf⁵, Cheng-Kun Du⁶, Yuji Shiba^{2

4}, Sachio Morimoto⁷, Mitsuhiko Yamada¹

Affiliations

¹ Department of Molecular Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan.
² Department of Biotechnology, Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan.
³ Department of Instrumental Analysis, Research Center for Supports to Advanced Science, Shinshu University, Matsumoto, Japan.
⁴ Department of Regenerative Science and Medicine, School of Medicine, Shinshu University, Matsumoto, Japan.
⁵ Division of Nephrology and Division of Vascular Endothelium and Microcirculation, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁶ Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.
⁷ School of Health Sciences Fukuoka, International University of Health and Welfare, Okawa, Japan.

Abstract

The treatment of pediatric heart failure is a long-standing unmet medical need. Angiotensin II supports mammalian perinatal circulation by activating cardiac L-type Ca²⁺ channels through angiotensin type 1 receptor (AT₁R) and β-arrestin. TRV027, a β-arrestin-biased AT₁R agonist, that has been reported to be safe but not effective for adult patients with heart failure, activates the AT₁R/β-arrestin pathway. We found that TRV027 evokes a long-acting positive inotropic effect specifically on immature cardiac myocytes through the AT₁R/β-arrestin/L-type Ca²⁺ channel pathway with minimum effect on heart rate, oxygen consumption, reactive oxygen species production, and aldosterone secretion. Thus, TRV027 could be utilized as a valuable drug specific for pediatric heart failure.

Keywords: AT1R, angiotensin type 1 receptor; AngII, angiotensin II; BBA, β-arrestin–biased angiotensin type 1 receptor agonist; ECG, electrocardiography; GPCR, G protein–coupled receptor; LTCC, CaV1.2 L-type Ca2+ channel; OCR, oxygen consumption rate; PHF, pediatric heart failure; ROS, reactive oxygen species; TRV027; UCG, ultrasound cardiogram; congenital dilated cardiomyopathy; hiPSC-CM, human induced pluripotent stem cell–derived cardiac myocyte; human induced pluripotent stem cell-derived cardiac myocytes; inotropic vasodilator; mNVCM, mouse neonatal ventricular cardiac myocyte; neonate; pediatric heart failure; β-arrestin–biased AT1 angiotensin receptor agonist.