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Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways |
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| Authors: | Crackower Michael A Oudit Gavin Y Kozieradzki Ivona Sarao Renu Sun Hui Sasaki Takehiko Hirsch Emilio Suzuki Akira Shioi Tetsuo Irie-Sasaki Junko Sah Rajan Cheng Hai-Ying M Rybin Vitalyi O Lembo Giuseppe Fratta Luigi Oliveira-dos-Santos Antonio J Benovic Jeffery L Kahn C Ronald Izumo Seigo Steinberg Susan F Wymann Matthias P Backx Peter H Penninger Josef M |
| Institution: | IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, c/o Dr. Bohr Gasse 7, A-1030, Vienna, Austria. |
| 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. |
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