title: Downregulation in GATA4 and Downstream Structural and Contractile Genes in the db/db Mouse Heart.
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.
authors.affiliation: Laboratory of Diabetes and Exercise Metabolism, Department of Physiology, Midwestern University, 19555 North 59th Avenue, Glendale, AZ, 85308, USA.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Broderick
authors.forename: Marek
authors.initials: M
authors.lastname: Jankowski
authors.forename: Donghao
authors.initials: D
authors.lastname: Wang
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Danalache
authors.forename: Cassandra R
authors.initials: CR
authors.lastname: Parrott
authors.forename: Jolanta
authors.initials: J
authors.lastname: Gutkowska