Background

In contrast to other cells in the heart, cardiac myocytes are considered to be terminally differentiated, meaning that the capacity for cell division is lost after the perinatal period. Without the capability for cell division, the heart can only respond to the increased demand for cardiac output associated with body growth by increasing its myocyte cell size. This normal ("physiologic") hypertrophic response is also characterized by the lack of activation of the fetal cardiac genetic program associated with "pathologic" cardiac hypertrophy, as observed in response to chronic pressure overload.

We believe that the identification of mechanisms regulating cardiomyocyte cell size during normal cardiac development will also give us important insight into the signaling pathways involved in cardiac hypertrophy. Much of our knowledge about the genetic pathways controlling cell and organ size comes from studies of dwarfism in humans, and more recently from gene targeting experiments in the mouse as well as from systematic genetic screenings of dwarfic Drosophila melanogaster mutants (reviewed in Weinkove & Leevers, 2000). Among the molecules identified as determinants of body and organ size are Drosophila homologues of insulin, the insulin receptor, the adapter protein (IRS), and p70 S6 kinase (Montagne et al., 1999), and phosphoinositide-3 kinase (PI3K) as an insulin-receptor downstream target (Leevers et al., 1996).

The insulin/IGF-IRS-PI3K-Akt pathway is highly conserved in evolution. To test whether this signaling cascade determines organ size in vertebrates, we have recently created mouse lines transgenic for constitutively active (caPI3K) and dominant-negative forms of PI3K (dnPI3K) (Shioi et al., 2000). Transgene expression is driven by the cardiac-specific a -myosin heavy chain (MHC) promoter. Both transgenic lines are characterized by moderate but highly consistent changes in heart size, despite the fact that body weight and the size of other organs are completely normal. caPI3K transgenic animals have hearts 20% larger than those of wild type littermates, whereas dnPI3K mice have hearts that are 17% smaller. The observed changes in heart size correlate with an appropriate increase or decrease in the size of transgenic cardiomyocytes. These hearts do not have cardiomyopathic changes, since the contractile function of transgenic hearts is normal, and signs of necrosis, apoptosis, or interstitial fibrosis are absent (see Physiology). These data suggest an autonomous role for PI3K in cell size regulation. Our goal is now to determine how activation of this system translates into changes in cell size by identifying the trigger and components of this signaling cascade.

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FVB wildtype mice were obtained from Charles River laboratories. For details about the generation of caPI3k and dnPI3k transgenic mice, please refer to Shioi et al., 2000.

We have generated transgenic mice expressing constitutively active or dominant-negative forms of PI3K. Transgene expression is driven by the a -myosin heavy chain (a -MHC) promoter (kindly provided by J. Robbins).

We will analyze expression profiles of heterozygous caPI3K and dnPI3K transgenic female mice between 5 and 14 months of age. Non-transgenic littermates will be analyzed at the same timepoints.

Shioi T, Kang PM, Douglas PS, Hampe J, Yballe CM, Lawitts J, Cantley LC, Izumo S. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 2000 Jun 1; 19(11):2537-48. (Abstract/Full Text)

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Page last modified: 01-Aug-2003