Phosphoinositide Depletion and Compensatory β-adrenergic Signaling in Angiotensin II-Induced Heart Disease: Protection Through PTEN Inhibition.

Contractile dysfunction, hypertrophy, and cell death during heart failure are linked to altered Ca(2+) handling, and elevated levels of the hormone angiotensin II (AngII), which signals through G(q)-coupled AT(1) receptors, initiating hydrolysis of PIP(2). Chronic elevation of AngII contributes to cardiac pathology, but the mechanisms linking sustained AngII signaling to heart dysfunction remain incompletely understood. Here, we demonstrate that chronic AngII exposure profoundly disrupts cardiac phosphoinositide homeostasis, triggering a cascade of cellular adaptations that ultimately impair cardiac function. Using in vivo AngII infusion combined with phospholipid mass spectrometry, super-resolution microscopy, and functional analyses, we show that sustained AngII signaling reduces PI(4,5)P(2) levels and triggers extensive redistribution of Ca(V)1.2 channels from t-tubules to various endosomal compartments. Despite this t-tubular channel loss, enhanced sympathetic drive maintains calcium currents and transients through increased channel phosphorylation via PKA and CaMKII pathways. However, this compensation proves insufficient as cardiac function progressively declines, marked by pathological hypertrophy, t-tubule disruption, and diastolic dysfunction. Notably, we identify depletion of PI(3,4,5)P(3) as a critical mediator of AngII-induced cardiac pathology. While preservation of PI(3,4,5)P(3) levels through PTEN inhibition did not prevent cellular remodeling or calcium handling changes, it protected against cardiac dysfunction, suggesting effects primarily through reduction of fibrosis. These findings reveal a complex interplay between phosphoinositide signaling, ion channel trafficking, and sympathetic activation in AngII-induced cardiac pathology. Moreover, they establish maintenance of PI(3,4,5)P(3) as a promising therapeutic strategy for hypertensive heart disease and as a potential protective adjunct therapy during clinical AngII administration.