Transcriptional activation of the glucose transporter GLUT1 in ventricular cardiac myocytes by hypertrophic agonists
Transcriptional activation of the glucose transporter GLUT1 in ventricular cardiac myocytes by hypertrophic agonists
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DOI：
10.1074/jbc.274.13.9006
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发表时间：
1999-03-26
影响因子：
4.8
通讯作者：
Thorburn, A
中科院分区：
文献类型：
--
作者：
Montessuit, C;Thorburn, A
心肌肥大与基础葡萄糖代谢增加有关。基础葡萄糖转运进入心肌细胞是由葡萄糖转运蛋白的GLUT 1亚型介导的，而GLUT 4亚型负责可调节的葡萄糖转运。用肥大激动剂12-O-十四烷酰佛波醇-13-乙酸酯或苯异丙基肾上腺素处理新生心肌细胞可增加Glut 1 mRNA相对于Glut 4 mRNA的表达。为了研究GLUT 1表达的转录调控，在Glut 1启动子的控制下，用荧光素酶报告基因构建体转染肌细胞。刺激细胞与12-O-十四烷酰佛波醇-13-乙酸酯或phenylethyl诱导转录的Glut 1启动子，这是抑制与促分裂原活化蛋白激酶磷酸酶CL 100和MKP-3的共转染。共转染的肌细胞与组成型活性版本的有和MEK 1或雌激素诱导型版本的Raf 1也刺激转录从Glut 1启动子。Glut 1启动子的肥大诱导也对磷脂酰肌醇3-激酶途径的抑制部分敏感，并通过与显性负性Ras共转染强烈抑制。因此，Ras激活和Ras下游途径介导心肌肥大过程中Glut 1启动子的诱导。
Myocardial hypertrophy is associated with increased basal glucose metabolism. Basal glucose transport into cardiac myocytes is mediated by the GLUT1 isoform of glucose transporters, whereas the GLUT4 isoform is responsible for regulatable glucose transport. Treatment of neonatal cardiac myocytes with the hypertrophic agonist 12-O-tetradecanoylphorbol-13-acetate or phenylephrine increased expression of Glut1 mRNA relative to Glut4 mRNA. To study the transcriptional regulation of GLUT1 expression, myocytes were transfected with luciferase reporter constructs under the control of the Glut1 promoter. Stimulation of the cells with 12-O-tetradecanoylphorbol-13-acetate or phenylephrine induced transcription from the Glut1 promoter, which was inhibited by cotransfection with the mitogen-activated protein kinase phosphatases CL100 and MKP-3. Cotransfection of the myocytes with constitutively active versions of has and MEK1 or an estrogen-inducible version of Raf1 also stimulated transcription from the Glut1 promoter. Hypertrophic induction of the Glut1 promoter was also partially sensitive to inhibition of the phosphatidylinositol 3-kinase pathway and was strongly inhibited by cotransfection with dominant-negative Ras. Thus, Ras activation and pathways downstream of Ras mediate induction of the Glut1 promoter during myocardial hypertrophy.