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 Ca2+ handling, and elevated levels of the hormone angiotensin II (AngII), which signals through Gq-coupled AT1 receptors, initiating hydrolysis of PIP2. 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)P2 levels and triggers extensive redistribution of CaV1.2 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)P3 as a critical mediator of AngII-induced cardiac pathology. While preservation of PI(3,4,5)P3 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)P3 as a promising therapeutic strategy for hypertensive heart disease and as a potential protective adjunct therapy during clinical AngII administration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/639781v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@126d18borg.highwire.dtl.DTLVardef@1870dadorg.highwire.dtl.DTLVardef@1931836org.highwire.dtl.DTLVardef@1ab23f_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO Graphical summary of chronic angiotensin II (AngII) signaling effects on cardiac calcium handling and fibrosis. Chronic AngII signaling through AT1R activates Gq-coupled signaling, leading to PI(4,5)P2 depletion that destabilizes CaV1.2 in the plasma membrane (PM), triggering their endocytosis and reduced channel numbers at the PM. The remaining CaV1.2 channels and RyR2 undergo compensatory phosphorylation by CaMKII and PKA, triggered by sympathetic activation (-AR signaling), leading to enhanced calcium-induced calcium release (CICR). Meanwhile, AngII promotes fibroblast-to-myofibroblast transition via M1 macrophage phenotype activation, increasing cardiac fibrosis. PTEN inhibition preserves PIP3 levels and promotes anti-inflammatory M2 macrophage activation, resulting in reduced fibrosis. These findings reveal a complex interplay between cardiac phosphoinositide signaling, calcium handling, and fibrotic remodeling with chronic AngII. AC, adenylyl cyclase; -AR, beta-adrenergic receptor; DAG, diacylglycerol; IP3, inositol trisphosphate; PLC, phospholipase C; PKA, protein kinase A; PTEN, phosphatase and tensin homolog. C_FIG