Downregulation in GATA4 and Downstream Structural and Contractile Genes in the db/db Mouse Heart.

ISRN endocrinology Pub Date : 2012-01-01 Epub Date: 2012-03-13 DOI:10.5402/2012/736860
Tom L Broderick, Marek Jankowski, Donghao Wang, Bogdan A Danalache, Cassandra R Parrott, Jolanta Gutkowska
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引用次数: 25

Abstract

Reduced expression of GATA4, a transcriptional factor for structural and cardioprotective genes, has been proposed as a factor contributing to the development of cardiomyopathy. We investigated whether the reduction of cardiac GATA4 expression reported in diabetes alters the expression of downstream genes, namely, atrial natriuretic peptide (ANP), B-type natriuretic, peptide (BNP), and α- and β-myosin heavy chain (MHC). db/db mice, a model of type 2 diabetes, with lean littermates serving as controls, were studied. db/db mice exhibited obesity, hyperglycemia, and reduced protein expression of cardiac GLUT4 and IRAP (insulin-regulated aminopeptidase), the structural protein cosecreted with GLUT4. Hearts from db/db mice had reduced protein expression of GATA4 (~35%) with accompanying reductions in mRNA expression of ANP (~40%), BNP (~85%), and α-MHC mRNA (~50%) whereas expression of β-MHC mRNA was increased by ~60%. Low GATA4 was not explained by an increased ligase or atrogin1 expression. CHIP protein content was modestly downregulated (27%) in db/db mice whereas mRNA and protein expression of the CHIP cochaperone HSP70 was significantly decreased in db/db hearts. Our results indicate that low GATA4 in db/db mouse heart is accompanied by reduced expression of GATA4-regulated cardioprotective and structural genes, which may explain the development of cardiomyopathy in diabetes.

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db/db小鼠心脏GATA4及下游结构和收缩基因的下调
GATA4是一种结构和心脏保护基因的转录因子,其表达减少被认为是导致心肌病发展的一个因素。我们研究了糖尿病患者心脏GATA4表达的降低是否会改变下游基因的表达,即心房利钠肽(ANP)、b型利钠肽(BNP)和α-和β-肌球蛋白重链(MHC)。研究人员对2型糖尿病模型Db / Db小鼠进行了研究,并将瘦窝鼠作为对照组。db/db小鼠表现出肥胖、高血糖、心脏GLUT4和IRAP(胰岛素调节的氨基肽酶,与GLUT4共分泌的结构蛋白)蛋白表达降低。db/db小鼠的心脏GATA4蛋白表达减少(~35%),ANP mRNA表达减少(~40%),BNP mRNA表达减少(~85%),α-MHC mRNA表达减少(~50%),而β-MHC mRNA表达增加~60%。低GATA4不是连接酶或atrogin1表达增加的原因。在db/db小鼠中,CHIP蛋白含量适度下调(27%),而在db/db心脏中,CHIP合作伙伴HSP70的mRNA和蛋白表达显著降低。我们的研究结果表明,在db/db小鼠心脏中,低GATA4伴随着GATA4调节的心脏保护和结构基因的表达减少,这可能解释了糖尿病心肌病的发展。
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