Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways

Cell. 2002 Sep 20;110(6):737-49. doi: 10.1016/s0092-8674(02)00969-8.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Cardiomegaly / genetics
  • Cardiomegaly / physiopathology
  • Cell Size
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • Ethanolamines / pharmacology
  • GTP-Binding Proteins / metabolism
  • Gene Expression Regulation
  • Genes, Tumor Suppressor
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Myocardial Contraction*
  • Myocardium / metabolism
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Adrenergic beta-Agonists
  • Ethanolamines
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • zinterol
  • Cyclic AMP
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • GTP-Binding Proteins