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

Expression of the wild type alpha subunit of G(q) (G(q)WT) in cardiomyocytes induces hypertrophy, whereas a constitutively active Galpha(q) subunit (G(q)Q209L) induces apoptosis. Akt phosphorylation increases with G(q)WT expression but is markedly attenuated in cardiomyocytes expressing G(q)Q209L or in those expressing G(q)WT and treated with agonist. A membrane-targeted Akt rescues G(q)Q209L-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(q)Q209L-expressing cardiomyocytes. Phosphatidylinositol 3,4,5-trisphosphate (PIP3), the primary regulator of Akt, increases significantly in G(q)WT-expressing cells but not in cardiomyocytes expressing G(q)Q209L. Levels of phosphatidylinositol 4,5-bisphosphate (PIP2), the immediate precursor of PIP3, are also markedly lower in G(q)Q209L-expressing compared to control cells. Expression of a G(q)Q209L mutant that has diminished capacity to activate phospholipase C does not decrease PIP2 or Akt or induce apoptosis. In transgenic mice with cardiac Galpha(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.