CARDIOPHYSIOLOGY Two PI3K Signals: One for Size and One for Strength

Cardiac hypertrophy is associated with many types of heart disease and can ultimately lead to cardiac decompensation and heart failure. One pathway important for the regulation of cell size is the phosphoinositide 3-kinase (PI3K) pathway acting through a signaling cascade that includes protein kinase B (PKB, also known as Akt), glycogen synthase kinase 3ß (GSK-3ß), and S6 kinase (p70^S6K). Crackower et al. analyzed mice with cardiac and skeletal muscle-targeted deletion of the lipid phosphatase PTEN (mckCRE-PTEN^/) that is responsible for termination of PI3K signaling by dephosphorylation of phosphatidylinositol 3-phosphate (PIP₃), the product of PI3K activity. The mckCRE-PTEN^/ mice had enlarged hearts without any evidence of cardiomyopathy or cardiac decompensation and enhanced phosphorylation of PKB, GSK-3ß, and p70^S6K. These mice also had decreased cardiac contractility. Increased cardiac contractility was evident in mice deficient for the G protein-coupled receptor (GPCR)-regulated isoform of the catalytic subunit of PI3K, p110. Double-mutant mice with both the cardiac PTEN deficiency and the p110 deficiency showed enlarged hearts without the decreased contractility seen in the mckCRE-PTEN^/ mice. The effect of the PTEN deficiency on heart size was eliminated in mice expressing dominant-negative p110, the isoform coupled to receptor tyrosine kinases. Thus, there appear to be two PI3K pathways: one that regulates size through PIP₃ produced by p110 and one that regulates contractility through PIP₃ produced by p110. Further investigation of the signaling pathway downstream of p110 suggested the involvement of adenosine 3',5'-monophosphate (cAMP) and regulation of the ß₂-adrenergic receptor in the enhanced contractility seen in the p110^-/- mice.

M. A. Crackower, G. Y. Oudit, I. Kozieradzki, R. Sarao, H. Sun, T. Sasaki, E. Hirsch, A. Suzuki, T. Shioi, J. Irie-Sasaki, R. Sah, H.-Y. M. Cheng, V. O. Rybin, A. J. Oliveira-dos-Santos, J. L. Benovic, C. R. Kahn, S. Izumo, S. F. Steinberg, M. P. Wymann, P. H. Backx, J. M. Penninger, Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110, 737-749 (2002). [Online Journal]