Markou Thomais, Cullingford Timothy E, Giraldo Alejandro, Weiss Sophie C, Alsafi Ali, Fuller Stephen J, Clerk Angela, Sugden Peter H
National Heart and Lung Institute Division, Faculty of Medicine, Imperial College London, Flowers Building, Armstrong Road, London SW7 2AZ, UK.
Cell Signal. 2008 Jan;20(1):206-18. doi: 10.1016/j.cellsig.2007.10.004. Epub 2007 Oct 12.
Inhibition of glycogen synthase kinase 3beta (GSK3beta) as a consequence of its phosphorylation by protein kinase B/Akt (PKB/Akt) has been implicated in cardiac myocyte hypertrophy in response to endothelin-1 or phenylephrine. We examined the regulation of GSK3alpha (which we show to constitute a significant proportion of the myocyte GSK3 pool) and GSK3beta in cardiac myocytes. Although endothelin increases phosphorylation of GSK3 and decreases its activity, the response is less than that induced by insulin (which does not promote cardiac myocyte hypertrophy). GSK3 phosphorylation induced by endothelin requires signalling through the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade and not the PKB/Akt pathway, whereas the reverse is true for insulin. Cardiac myocyte hypertrophy involves changes in morphology, and in gene and protein expression. The potent GSK3 inhibitor 1-azakenpaullone increases myocyte area as a consequence of increased cell length whereas phenylephrine increases both length and width. Azakenpaullone or insulin promotes AP1 transcription factor binding to an AP1 consensus oligonucleotide, but this was significantly less than that induced by endothelin and derived principally from increased binding of JunB protein, the expression of which was increased. Azakenpaullone promotes significant changes in gene expression (assessed by Affymetrix microarrays), but the overall response is less than with endothelin and there is little overlap between the genes identified. Thus, although GSK3 may contribute to cardiac myocyte hypertrophy in some respects (and presumably plays an important role in myocyte metabolism), it does not appear to contribute as significantly to the response induced by endothelin as has been maintained.
糖原合酶激酶3β（GSK3β）被蛋白激酶B/Akt（PKB/Akt）磷酸化后受到抑制，这与心肌细胞对内皮素-1或去氧肾上腺素的肥大反应有关。我们研究了心肌细胞中GSK3α（我们发现它在心肌细胞GSK3总量中占相当大比例）和GSK3β的调控。尽管内皮素增加了GSK3的磷酸化并降低了其活性，但其反应小于胰岛素诱导的反应（胰岛素不会促进心肌细胞肥大）。内皮素诱导的GSK3磷酸化需要通过细胞外信号调节激酶1/2（ERK1/2）级联信号传导，而不是PKB/Akt途径，而胰岛素的情况则相反。心肌细胞肥大涉及形态、基因和蛋白质表达的变化。强效GSK3抑制剂1-氮杂肯帕罗因细胞长度增加导致心肌细胞面积增大，而去氧肾上腺素则增加细胞长度和宽度。氮杂肯帕罗因或胰岛素促进AP1转录因子与AP1共有寡核苷酸结合，但这明显少于内皮素诱导的结合，且主要源于JunB蛋白结合增加，JunB蛋白的表达也增加。氮杂肯帕罗因促进基因表达发生显著变化（通过Affymetrix微阵列评估），但总体反应小于内皮素，且所鉴定的基因之间几乎没有重叠。因此，尽管GSK3可能在某些方面促成心肌细胞肥大（并且可能在心肌细胞代谢中起重要作用），但它似乎对内皮素诱导的反应贡献不如之前认为的那么显著。
