Key result
In db/db mice, reduced cardiac GATA4 expression (~35%) was accompanied by decreased mRNA expression of ANP (~40%), BNP (~85%), and α-MHC (~50%), and increased β-MHC (~60%).
Reduced GATA4 expression in the diabetic mouse heart is associated with downregulation of cardioprotective and structural genes, providing a potential mechanism for diabetic cardiomyopathy.
Supports GATA4 downregulation in diabetic cardiomyopathy models; hypothesis-generating for human mechanistic and therapeutic studies.
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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Broderick et al. (2012) studied Type 2 diabetes and cardiomyopathy. db/db genotype (type 2 diabetes model) vs. Lean littermates was evaluated on Expression of GATA4 and downstream structural and contractile genes. In db/db mice, reduced cardiac GATA4 expression (~35%) was accompanied by decreased mRNA expression of ANP (~40%), BNP (~85%), and α-MHC (~50%), and increased β-MHC (~60%).
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