Akt-mediated cardiomyocyte survival pathways are compromised by Gα_q-induced phosphoinositide 4,5-bisphosphate depletion

Expression of the wild type α subunit of G_q (G _qWT) in cardiomyocytes induces hypertrophy, whereas a constitutively active Gα_q subunit (G_qQ209L) induces apoptosis. Akt phosphorylation increases with G_qWT expression but is markedly attenuated in cardiomyocytes expressing G_qQ209L or in those expressing G_qWT and treated with agonist. A membrane-targeted Akt rescues G_qQ209L-expressing cardiomyocytes from apoptotic cell death. In contrast, leukemia inhibitory factor fails to activate Akt or promote cell survival in these cells. Association of Akt and PDK-1 with the membrane is also diminished in G_qQ209L-expressing cardiomyocytes. Phosphatidylinositol 3,4,5-trisphosphate (PIP₃), the primary regulator of Akt, increases significantly in G_qWT-expressing cells but not in cardiomyocytes expressing G_qQ209L. Levels of phosphatidylinositol 4,5-bisphosphate (PIP₂), the immediate precursor of PIP₃, are also markedly lower in G _qQ209L-expressing compared to control cells. Expression of a G _qQ209L mutant that has diminished capacity to activate phospholipase C does not decrease PIP₂ or Akt or induce apoptosis. In transgenic mice with cardiac Gα_q overexpression, heart failure and increased cardiomyocyte apoptosis develop during the peripartal period. Akt phosphorylation and PIP₂ levels decrease concomitantly. Our findings suggest that an Akt-mediated cell survival pathway is compromised by the diminished availability of PIP₂ elicited by pathological levels of G_q activity.