Regulation of Cardiomyocyte Proliferation and Myocardial Growth During Development by FOXO Transcription Factors

作者：Heather J. Evans‐Anderson, Christina M. Alfieri, Katherine E. Yutzey · 发表于：Circulation Research · 年份：2008 · DOI：10.1161/circresaha.107.163428 · 被引用次数：224 · 研究领域：FOXO transcription factor regulation、Multilevel Inverters and Converters、Pluripotent Stem Cells Research

Cardiomyocytes actively proliferate during embryogenesis and withdraw from the cell cycle during neonatal stages. FOXO (Forkhead O) transcription factors are a direct target of phosphatidylinositol-3 kinase/AKT signaling in skeletal and smooth muscle and regulate expression of the Cip/Kip family of cyclin kinase inhibitors in other cell types; however, the interaction of phosphatidylinositol-3 kinase/AKT signaling, FOXO transcription factors, and cyclin kinase inhibitor expression has not been reported for the developing heart. Here, we show that FOXO1 and FOXO3 are expressed in the developing myocardium concomitant with increased cyclin kinase inhibitor expression from embryonic to neonatal stages. Cell culture studies show that embryonic cardiomyocytes are responsive to insulin-like growth factor 1 stimulation, which results in the induction of the phosphatidylinositol-3 kinase/AKT pathway, cytoplasmic localization of FOXO proteins, and increased myocyte proliferation. Likewise, adenoviral-mediated expression of AKT promotes cardiomyocyte proliferation and cytoplasmic localization of FOXO. In contrast, increased expression of FOXO1 negatively affects myocyte proliferation. In vivo myocyte-specific transgenic expression of FOXO1 during heart development causes embryonic lethality at embryonic day 10.5 because of severe myocardial defects that coincide with premature activation of p21(cip1), p27(kip1), and p57(kip2) and decreased myocyte proliferation. Transgenic expression o...