Mechanisms underlying the efficacy and safety of β-arrestin-biased AT₁ agonists as therapeutics for neonatal and infantile heart failure

Abstract

Angiotensin II (AngII) regulates the circulation mainly through its type 1 receptors (AT₁R) coupled to G proteins and β-arrestins. Here, we demonstrate the recent findings on the roles of AT₁R/β-arrestins pathway in heart and kidney during developmental periods. We previously reported that a β-arrestin-biased AT₁ agonist (BBA), which activates β-arrestins but inhibits G proteins, induced a positive inotropic effect on neonatal mice almost without an increase in heart rate or oxygen consumption. This effect was also observed in neonatal mice harboring a cardiac troponin T mutation that causes dilated cardiomyopathy in humans. Although the majority of these homozygous littermates died before weaning, we found that BBA treatment alleviated their decline in cardiac function and improved the survival rate. In contrast, an AT₁R blocker (ARB), which inhibits both β-arrestins and G proteins, not only failed to rescue the survival rate but also severely hampered the postnatal metanephrogenesis in wildtype littermates. ARB-treated mice exhibited marked abnormalities of the cortex/medulla and renal failure symptoms. This renal toxicity was not observed with BBA. Therefore, it is likely that AngII exerts its prosurvival cardiovascular and renal effects on preweaning mammals mainly through β-arrestins, but not G proteins, coupled to AT₁R.