TY - JOUR
T1 - Akt-mediated cardiomyocyte survival pathways are compromised by Gαq-induced phosphoinositide 4,5-bisphosphate depletion
AU - Howes, Amy L.
AU - Arthur, Jane F.
AU - Zhang, Tong
AU - Miyamoto, Shigeki
AU - Adams, John W.
AU - Dorn, Gerald W.
AU - Woodcock, Elizabeth A.
AU - Brown, Joan Heller
PY - 2003/10/10
Y1 - 2003/10/10
N2 - Expression of the wild type α subunit of Gq (G qWT) in cardiomyocytes induces hypertrophy, whereas a constitutively active Gαq subunit (GqQ209L) induces apoptosis. Akt phosphorylation increases with GqWT expression but is markedly attenuated in cardiomyocytes expressing GqQ209L or in those expressing GqWT and treated with agonist. A membrane-targeted Akt rescues GqQ209L-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 GqQ209L-expressing cardiomyocytes. Phosphatidylinositol 3,4,5-trisphosphate (PIP3), the primary regulator of Akt, increases significantly in GqWT-expressing cells but not in cardiomyocytes expressing GqQ209L. 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 Gαq 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 Gq activity.
AB - Expression of the wild type α subunit of Gq (G qWT) in cardiomyocytes induces hypertrophy, whereas a constitutively active Gαq subunit (GqQ209L) induces apoptosis. Akt phosphorylation increases with GqWT expression but is markedly attenuated in cardiomyocytes expressing GqQ209L or in those expressing GqWT and treated with agonist. A membrane-targeted Akt rescues GqQ209L-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 GqQ209L-expressing cardiomyocytes. Phosphatidylinositol 3,4,5-trisphosphate (PIP3), the primary regulator of Akt, increases significantly in GqWT-expressing cells but not in cardiomyocytes expressing GqQ209L. 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 Gαq 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 Gq activity.
UR - http://www.scopus.com/inward/record.url?scp=0141890280&partnerID=8YFLogxK
U2 - 10.1074/jbc.M305964200
DO - 10.1074/jbc.M305964200
M3 - Article
C2 - 12900409
AN - SCOPUS:0141890280
SN - 0021-9258
VL - 278
SP - 40343
EP - 40351
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 41
ER -