Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute beta-adrenergic stimulation.
Signaling pathways underlying transition of cardiomyocyte growth from hyperplasia in fetal/newborn to hypertrophy in postnatal/adult hearts are not well understood. We have shown that beta-adrenergic receptor (beta-AR)-mediated regulation of neonatal cardiomyocyte proliferation involves p70 ribosomal protein S6 kinase (p70S6K). Here we examined the ontogeny of phosphoinositide 3-kinase (PI3K)/p70S6K signaling pathway in rat hearts and investigated the influence of beta-AR on this pathway during development. Cardiac PI3K and p70S6K1 activities were high in the embryonic day 20 fetus, decreased gradually postnatally, and were low in the adult. In contrast, p70S6K2 was barely detectable. Phosphorylation of p70S6K1, Akt, and phosphoinositide-dependent protein kinase 1 were markedly increased in late gestation and early postnatal life but not in adult hearts. Phosphatase and tensin homolog on chromosome 10 (PTEN), a negative regulator of PI3K, was highly expressed in adult hearts but only at low levels and mostly in the phosphorylated (inactivated) form in the fetus. Beta-AR stimulation resulted in increased cardiac p70S6K1 activity only in animals > or = 2 wk old, whereas Akt level was increased in all developmental stages tested. These increases were accompanied by increased Bcl-2 associated death promoter (Ser136) phosphorylation without changes in PTEN level. Thus there is globally high input of cardiac PI3K signaling during the fetal-neonatal transition period. Inactivation of PTEN may in part contribute to the high activity of PI3K signaling, which coincides with the period of high cardiomyocyte proliferation. Beta-AR stimulation activates cardiac p70S6K1 and Akt in postnatal animals and may activate cardiac survival signals. These data provide further evidence for the importance of beta-AR and PI3K signaling in the regulation of cardiac growth during development.
Tseng
Yi-Tang
YT
Dept. of Pediatrics, Women and Infants Hospital of Rhode Island, Brown Medical School, Providence, RI 02905, USA. ytseng@wihri.org
Yano
Naohiro
N
Rojan
Adam
A
Stabila
Joan P
JP
McGonnigal
Bethany G
BG
Ianus
Vlad
V
Wadhawan
Rajan
R
Padbury
James F
JF
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000375:Aging / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D006321:Heart / Q000187:drug effects / Q000254:growth & development* / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D019869:Phosphatidylinositol 3-Kinases