Regulation of cardiomyocyte proliferation and myocardial growth during development by FOXO transcription factors
Regulation of cardiomyocyte proliferation and myocardial growth during development by FOXO transcription factors
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DOI：
10.1161/circresaha.107.163428
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发表时间：
2008-03-28
影响因子：
20.1
通讯作者：
Yutzey, Katherine E.
中科院分区：
文献类型：
--
作者：
Evans-Anderson, Heather J.;Alfieri, Christina M.;Yutzey, Katherine E.
心肌细胞在胚胎发生期间活跃地增殖，并且在新生阶段退出细胞周期。FOXO（Forkhead O）转录因子是骨骼肌和平滑肌中磷脂酰肌醇-3激酶/AKT信号传导的直接靶点，并调节其他细胞类型中细胞周期蛋白激酶抑制剂的Cip/Kip家族的表达;然而，对于发育中的心脏，尚未报道磷脂酰肌醇-3激酶/AKT信号传导、FOXO转录因子和细胞周期蛋白激酶抑制剂表达的相互作用。在这里，我们表明，FOXO 1和FOXO 3的表达在发展中的心肌细胞周期蛋白激酶抑制剂的表达增加，从胚胎到新生儿阶段。细胞培养研究表明，胚胎心肌细胞对胰岛素样生长因子1刺激有反应，这导致磷脂酰肌醇-3激酶/AKT途径的诱导、FOXO蛋白质的细胞质定位和肌细胞增殖的增加。同样，腺病毒介导的AKT表达促进心肌细胞增殖和FOXO的细胞质定位。相反，FOXO 1表达的增加会对肌细胞增殖产生负面影响。在心脏发育过程中，体内肌细胞特异性FOXO 1转基因表达导致胚胎在胚胎第10.5天死亡，因为严重的心肌缺陷与p21（cip 1）、p27（kip 1）和p57（kip 2）的过早激活以及肌细胞增殖减少相一致。转基因显性失活FOXO 1基因在心肌细胞中的表达对胚胎10.5天的心脏发育无明显影响，但到胚胎沿着出现心肌形态异常，细胞周期蛋白激酶抑制剂表达降低，心肌细胞增殖增加。这些数据支持FOXO转录因子作为心脏发育过程中心肌细胞增殖的负调节因子和新生儿细胞周期退出的促进因子。
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 of dominant negative FOXO1 in cardiomyocytes does not obviously affect heart development at embryonic day 10.5, but results in abnormal morphology of the myocardium by embryonic day 18.5 along with decreased cyclin kinase inhibitor expression and increased myocyte proliferation. These data support FOXO transcription factors as negative regulators of cardiomyocyte proliferation and promoters of neonatal cell cycle withdrawal during heart development.