title: Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways.
abstract: 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.
authors.affiliation: IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, c/o Dr. Bohr Gasse 7, A-1030, Vienna, Austria.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Crackower
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.forename: Ivona
authors.initials: I
authors.lastname: Kozieradzki
authors.forename: Renu
authors.initials: R
authors.lastname: Sarao
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shioi
authors.forename: Junko
authors.initials: J
authors.lastname: Irie-Sasaki
authors.forename: Rajan
authors.initials: R
authors.lastname: Sah
authors.forename: Hai-Ying M
authors.initials: HY
authors.lastname: Cheng
authors.forename: Vitalyi O
authors.initials: VO
authors.lastname: Rybin
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
authors.forename: Luigi
authors.initials: L
authors.lastname: Fratta
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Oliveira-dos-Santos
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Benovic
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Seigo
authors.initials: S
authors.lastname: Izumo
authors.forename: Susan F
authors.initials: SF
authors.lastname: Steinberg
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Wymann
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: 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*
chemical_list: 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