Peptide ACTY116 attenuates noradrenaline-induced cardiac hypertrophy and improves heart function by biasing α1B-adrenergic receptor signaling

Myocardial hypertrophy is a critical precursor to heart failure, a condition with limited targeted therapeutic options. Pathological cardiac hypertrophy is primarily driven by the Gαq protein pathway. Current treatments often lack specificity or efficacy in directly addressing this underlying mechanism. ACTY116 is a novel peptide designed to competitively inhibit the Gαq protein, offering a potential new strategy to mitigate hypertrophy by targeting this key driver.

Researchers investigated ACTY116 in a noradrenaline-stimulated mouse model of myocardial hypertrophy and in AC16 cardiomyocytes. The study aimed to evaluate its therapeutic potential and mechanistic profile. Mechanistic analyses included assessing Gαq-dependent pathways such as calcium influx and NFAT2 nuclear translocation. They also examined β-arrestin recruitment, receptor internalization, and the dynamics of ERK1/2 phosphorylation to understand the peptide's biased signaling properties.

In noradrenaline-stimulated mice, ACTY116 significantly attenuated myocardial hypertrophy and improved cardiac function. Mechanistically, ACTY116 demonstrated biased signaling by inhibiting Gαq-dependent pathways, including calcium influx and NFAT2 nuclear translocation. Simultaneously, it promoted β-arrestin recruitment and α1B-adrenergic receptor internalization. This biased action was further supported by selective inhibition of rapid ERK1/2 phosphorylation (G-protein-mediated) and activation of sustained ERK1/2 phosphorylation (β-arrestin-dependent).