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: CM hypertrophy was induced by angiotensin II in isolated adult mouse CMs, with hypertrophy assessed by cell surface area and protein synthesis. PDE10A inactivation was achieved through PDE10A knockout or inhibition with TP-10. Various pharmacological agonists/antagonists, genetic mutants, and knockout models of D 2 R (dopamine receptor D2) and A 2A R (adenosine A 2A receptor) were used to study the role of A 2A R-D 2 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: We demonstrated that the antihypertrophic effect of PDE10A inactivation is specifically dependent on cAMP/PKA (protein kinase A) signaling. Importantly, we discovered an A 2A R-D 2 R heterodimer and its association with PDE10A in CMs. The A 2A R-D 2 R heterodimer mediates the βarr2 (beta-arrestin 2)–biased D 2 R signaling, and activating D 2 R-biased signaling antagonizes cardiac hypertrophy and dysfunction. PDE10A deficiency or inhibition enhanced A 2A R-D 2 R heterodimerization, promoting βarr2-biased D 2 R signaling and downstream PP2A (protein phosphatase 2A)-B56δ activation through increased A 2A R/cAMP/PKA–mediated D 2 R phosphorylation. PDE10A inactivation inhibits stress signal–induced HDAC5 (histone deacetylase 5) nuclear export and phosphorylation, which are dependent on PP2A. Genetic and pharmacological approaches in animal models confirmed the critical roles of A 2A R-D 2 R heterodimerization, D 2 R phosphorylation, and biased D 2 R signaling in vivo. Furthermore, combining PDE10A inhibition with A 2A R or D 2 R-biased agonism produced synergistic antihypertrophic effects, highlighting their novel therapeutic potential. CONCLUSIONS: Our findings reveal A 2A R-D 2 R dimerization and βarr2-biased D 2 R signaling as novel and critical mechanisms for counteracting pathological CM hypertrophy and cardiac dysfunction. PDE10A acts as a pivotal negative regulator of this signaling axis. Targeting PDE10A, A 2A R-D 2 R/βarr2 signaling, or both offers potentially novel therapeutic strategies for combating pathological cardiac remodeling and cardiac dysfunction.