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Molecular and Cellular Biology, November 2005, p. 9491-9502, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9491-9502.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Class IA Phosphoinositide 3-Kinase Regulates Heart Size and Physiological Cardiac Hypertrophy

Ji Luo,1,§ Julie R. McMullen,2,{dagger},§ Cassandra L. Sobkiw,1 Li Zhang,2 Adam L. Dorfman,3 Megan C. Sherwood,3 M. Nicole Logsdon,1 James W. Horner,3 Ronald A. DePinho,4 Seigo Izumo,2,{ddagger} and Lewis C. Cantley1*

Department of Systems Biology, Harvard Medical School, and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115,1 Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215,2 Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts 02115,3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 021154

Received 2 June 2005/ Returned for modification 28 July 2005/ Accepted 16 August 2005

Class IA phosphoinositide 3-kinases (PI3Ks) are activated by growth factor receptors, and they regulate, among other processes, cell growth and organ size. Studies using transgenic mice overexpressing constitutively active and dominant negative forms of the p110{alpha} catalytic subunit of class IA PI3K have implicated the role of this enzyme in regulating heart size and physiological cardiac hypertrophy. To further understand the role of class IA PI3K in controlling heart growth and to circumvent potential complications from the overexpression of dominant negative and constitutively active proteins, we generated mice with muscle-specific deletion of the p85{alpha} regulatory subunit and germ line deletion of the p85ß regulatory subunit of class IA PI3K. Here we show that mice with cardiac deletion of both p85 subunits exhibit attenuated Akt signaling in the heart, reduced heart size, and altered cardiac gene expression. Furthermore, exercise-induced cardiac hypertrophy is also attenuated in the p85 knockout hearts. Despite such defects in postnatal developmental growth and physiological hypertrophy, the p85 knockout hearts exhibit normal contractility and myocardial histology. Our results therefore provide strong genetic evidence that class IA PI3Ks are critical regulators for the developmental growth and physiological hypertrophy of the heart.

* Corresponding author. Mailing address: Division of Signal Transduction, Beth Israel Deaconess Medical Center, 77 Avenue Louis Pasteur, 10th Floor, Boston, MA 02115. Phone: (617) 667-0947. Fax: (617) 667-0957. E-mail: lewis_cantley{at}hms.harvard.edu.

§ These authors contributed equally to this work.

{dagger} Present address: Baker Heart Research Institute, Melbourne, Victoria 8008, Australia.

{ddagger} Present address: Novartis Institutes for Biomedical Research, Cambridge, MA 02139.

Molecular and Cellular Biology, November 2005, p. 9491-9502, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9491-9502.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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