Abstract

Background PPP2R3A is a key regulatory subunit of the PP2A B’’ family that encodes PR130 and PR72, two isoforms highly expressed in the heart. It has been implicated in heart failure and represents a potential molecular hub connecting pathological remodeling to disease progression. However, its functional dynamics in pressure overload-induced heart failure remain unclear. This study aims to investigate the expression changes and regulatory mechanisms of PPP2R3A in pressure overload-induced decompensated heart failure. Methods A chronic pressure overload model was established in C57BL/6J mice using transverse aortic constriction (TAC), and cardiac function and remodeling were assessed by echocardiography and histological analyses. In vitro, PPP2R3A was silenced or overexpressed in H9c2 cardiomyocytes to evaluate its effects on transcription, viability, and apoptosis. Protein interactions and downstream signaling were examined using co-immunoprecipitation, GST pull-down, and Western blotting. Results PPP2R3A expression was markedly downregulated in the TAC model, accompanied by impaired systolic function, pathological hypertrophy, and fibrosis. In cardiomyocytes, PPP2R3A knockdown exacerbated apoptosis and reduced viability, whereas overexpression promoted robust survival. Mechanistically, PPP2R3A stabilized the β-catenin destruction complex, thereby suppressing canonical Wnt/β-catenin signaling and preventing maladaptive β-catenin-driven transcription. Proteomic assays identified a direct interaction between PPP2R3A and RGS19, with PPP2R3A negatively regulating RGS19 protein abundance and Ser/Thr phosphorylation. Conclusions PPP2R3A protects the heart against pressure overload-induced heart failure by stabilizing the β-catenin degradation complex and limiting maladaptive Wnt/β-catenin signaling. Its regulation of RGS19 reveals a novel axis in the transition from compensated to decompensated heart failure, highlighting PPP2R3A as a potential therapeutic target.