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. PI3Kα mediates the alteration in cell size while PI3Kγ acts as a negative regulator of cardiac contractility. Mechanistically, PI3Kγ 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-PI3Kγ pathway in the modulation of heart muscle contractility.
Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways / Michael A., Crackower; Gavin Y., Oudit; Ivona, Kozieradzki; Renu, Sarao; Hui, Sun; Takehiko, Sasaki; Emilio, Hirsch; Akira, Suzuki; Tetsuo, Shioi; T., Irie Sasaki; Lembo, Giuseppe; Luigi, Fratta; Oliveira Dos Santos A. J., Benovic Jl; Kahn Cr S., Izumo; Steinberg S. F., Wymann Mp; P. H., Penninger Jm Backx. - In: CELL. - ISSN 0092-8674. - STAMPA. - 110:6(2002), pp. 737-749. [10.1016/s0092-8674(02)00969-8]
Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways
LEMBO, Giuseppe;
2002
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. PI3Kα mediates the alteration in cell size while PI3Kγ acts as a negative regulator of cardiac contractility. Mechanistically, PI3Kγ 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-PI3Kγ pathway in the modulation of heart muscle contractility.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
