Broderick Tom L, Jankowski Marek, Wang Donghao, Danalache Bogdan A, Parrott Cassandra R, Gutkowska Jolanta
Laboratory of Diabetes and Exercise Metabolism, Department of Physiology, Midwestern University, 19555 North 59th Avenue, Glendale, AZ, 85308, USA.
ISRN Endocrinol. 2012;2012:736860. doi: 10.5402/2012/736860. Epub 2012 Mar 13.
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.
GATA4是一种负责结构和心脏保护基因的转录因子，其表达降低被认为是导致心肌病发展的一个因素。我们研究了糖尿病中所报道的心脏GATA4表达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）以及α和β肌球蛋白重链（MHC）。我们以瘦的同窝小鼠作为对照，对2型糖尿病模型db/db小鼠进行了研究。db/db小鼠表现出肥胖、高血糖，且心脏葡萄糖转运蛋白4（GLUT4）和胰岛素调节氨肽酶（IRAP，与GLUT4共同分泌的结构蛋白）的蛋白表达降低。db/db小鼠心脏中GATA4的蛋白表达降低了约35%，同时ANP的mRNA表达降低了约40%，BNP降低了约85%，α-MHC mRNA降低了约50%，而β-MHC mRNA的表达增加了约60%。GATA4表达降低并非由连接酶或atrogin1表达增加所致。db/db小鼠中CHIP蛋白含量适度下调（27%），而db/db小鼠心脏中CHIP伴侣蛋白HSP70的mRNA和蛋白表达显著降低。我们的结果表明，db/db小鼠心脏中GATA4水平降低伴随着GATA4调节的心脏保护和结构基因表达降低，这可能解释了糖尿病性心肌病的发生发展。
