Contractile dysfunction, hypertrophy, and cell death during heart failure are linked to altered Ca Mice received 1-week infusions of AngII, bisperoxovanadium 1,10 phenanthroline, both, or saline via osmotic minipumps. We used mass spectrometry, super-resolution microscopy, electrophysiology, confocal imaging, immunoblot, echocardiography, and histology to assess PI levels, Ca Chronic AngII infusion caused widespread PI imbalance, reducing PI, phosphatidylinositol (4,5)-bisphosphate, and phosphatidylinositol (3,4,5)-trisphosphate levels. Ca These findings reveal a complex interplay between PI signaling, ion channel trafficking, and compensatory phospho-regulation in AngII-induced cardiac pathology. We establish phosphatidylinositol (3,4,5)-trisphosphate depletion as a critical link between chronic AngII signaling and cardiac dysfunction. The dissociation between persistent cellular remodeling and preserved organ function with PTEN inhibition reveals that cardioprotection occurs primarily through reduced fibrosis. PTEN inhibition, thus, emerges as a promising therapeutic strategy for heart failure associated with pathological renin-angiotensin system activation, with potential to complement existing therapies by targeting antifibrotic responses.