Open AccessClass IA Phosphoinositide 3-Kinase Regulates Heart Size and Physiological Cardiac Hypertrophy
Author(s) -
Ji Luo,
Julie R. McMullen,
Cassandra L. Sobkiw,
Li Zhang,
Adam L. Dorfman,
Megan C. Sherwood,
M. Nicole Logsdon,
James W. Horner,
Ronald A. DePinho,
Seigo Izumo,
Lewis C. Cantley
Publication year - 2005
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.25.21.9491-9502.2005
Subject(s) - biology , phosphoinositide 3 kinase , muscle hypertrophy , knockout mouse , pi3k/akt/mtor pathway , endocrinology , medicine , protein kinase b , contractility , kinase , protein subunit , microbiology and biotechnology , phosphorylation , signal transduction , receptor , gene , genetics
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 p110α 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 p85α regulatory subunit and germ line deletion of the p85β 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.