Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways.
The PTEN/PI3K signaling pathway regulates a vast array of fundamental cellular responses. We show that cardiomyocyte-specific inactivation of tumor suppressor PTEN results in hypertrophy, and unexpectedly, a dramatic decrease in cardiac contractility. Analysis of double-mutant mice revealed that the cardiac hypertrophy and the contractility defects could be genetically uncoupled. PI3Kalpha mediates the alteration in cell size while PI3Kgamma acts as a negative regulator of cardiac contractility. Mechanistically, PI3Kgamma inhibits cAMP production and hypercontractility can be reverted by blocking cAMP function. These data show that PTEN has an important in vivo role in cardiomyocyte hypertrophy and GPCR signaling and identify a function for the PTEN-PI3Kgamma pathway in the modulation of heart muscle contractility.
Crackower
Michael A
MA
IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, c/o Dr. Bohr Gasse 7, A-1030, Vienna, Austria.
Oudit
Gavin Y
GY
Kozieradzki
Ivona
I
Sarao
Renu
R
Sun
Hui
H
Sasaki
Takehiko
T
Hirsch
Emilio
E
Suzuki
Akira
A
Shioi
Tetsuo
T
Irie-Sasaki
Junko
J
Sah
Rajan
R
Cheng
Hai-Ying M
HY
Rybin
Vitalyi O
VO
Lembo
Giuseppe
G
Fratta
Luigi
L
Oliveira-dos-Santos
Antonio J
AJ
Benovic
Jeffery L
JL
Kahn
C Ronald
CR
Izumo
Seigo
S
Steinberg
Susan F
SF
Wymann
Matthias P
MP
Backx
Peter H
PH
Penninger
Josef M
JM
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology; D048429:Cell Size; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D000242:Cyclic AMP; D004983:Ethanolamines; D019204:GTP-Binding Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; C002904:zinterol