Role of A 2A R-D2R Dimerization and D 2 R-Biased Signaling in PDE10A-Mediated Cardiac Hypertrophy

BACKGROUND: Pathological cardiomyocyte (CM) hypertrophy is a hallmark of dilated cardiomyopathy and heart failure, driven by mechanical or neurohumoral stress. Although we previously demonstrated PDE10A (phosphodiesterase 10A) as a critical contributor and potential therapeutic target in pathological cardiac remodeling and dysfunction, the underlying mechanisms remain unclear. Here, we investigated the specific signaling pathways and sources of cyclic nucleotides modulated by PDE10A in CM hypertrophy. METHODS: R heterodimer and downstream signaling in CM hypertrophy in vitro and in vivo. Viral vectors were used to manipulate protein or small hairpin RNA expression targeting key signaling molecules. RESULTS: R-biased agonism produced synergistic antihypertrophic effects, highlighting their novel therapeutic potential. CONCLUSIONS: R/βarr2 signaling, or both offers potentially novel therapeutic strategies for combating pathological cardiac remodeling and cardiac dysfunction.