The peptide ACTY116 improved noradrenaline-induced cardiac hypertrophy and enhanced cardiac function by biasing receptor signaling toward the β-arrestin and against the Gαq protein

Abstract Objectives Myocardial hypertrophy, is a major precursor to heart failure, is characterized by a lack of targeted therapeutic efficacy. ACTY116, investigated by our group, is a novel peptide designed to competitively inhibit the Gαq protein, known as the key driver of pathological cardiac hypertrophy. This study aimed to evaluate the therapeutic potential and mechanistic profile of ACTY116. Methods The effects of ACTY116 were investigated in a noradrenaline-stimulated mouse model of myocardial hypertrophy and in AC16 cardiomyocytes. Mechanistic analyses included assessment of Gαq-dependent pathways (calcium influx, NFAT2 nuclear translocation), β-arrestin recruitment, receptor internalization, and the dynamics of ERK1/2 phosphorylation. Key findings In noradrenaline-stimulated mice, ACTY116 significantly attenuated myocardial hypertrophy and improved cardiac function. Mechanistically, ACTY116 exhibited biased signaling: it inhibited Gαq-dependent pathways, including calcium influx and NFAT2 nuclear translocation, while promoting β-arrestin recruitment and α1B-adrenergic receptor internalization. This biased signaling was evidenced by selective inhibition of rapid ERK1/2 phosphorylation (G-protein-mediated) and activation of sustained ERK1/2 phosphorylation (β-arrestin-dependent). In AC16 cardiomyocytes, ACTY116 reduced cell hypertrophy and enhanced survival. Conclusions These findings identified ACTY116 as a promising cardioprotective agent with unique biased agonism, offering a novel therapeutic strategy for cardiac hypertrophy.