ABSTRACT
GATA4 is a transcriptional factor expressed in heart that regulates the synthesis of structural and cardioprotective genes. We have demonstrated that low GATA4 expression in the db/db mouse heart is associated with reduced expression of key downstream genes, including oxytocin (OT) natriuretic peptide (A-, B-type), nitric oxide synthase (eNOS), and myosin heavy chain (α-MHC). In this study, the effect of exercise on GATA4 expression and related genes was determined in the db/db mouse, a model that represents human type 2 diabetes. Vascular endothelial growth factor (VEGF) and hypoxia-induced factor-α expression were also measured after 8 weeks of treadmill running. Compared with control littermates, db/db mice exhibited hyperglycemia and obesity, and exercise failed to improve these parameters. GATA4 expression was reduced in db/db hearts and this was associated with reduced expression of OT, OTR, ANP, BNP, eNOS, α-MHC, and ratio of α- to ß-MHC, whereas mRNA expression of ß-MHC and VEGF remained unchanged compared with control hearts. Exercise training increased GATA4 expression (mRNA and protein) but most genes regulated by GATA4 were not observed to increase accordingly. However, protein expression of eNOS, mRNA expression of α-MHC, ratio of α- to ß-MHC, and protein expression of VEGF were increased in db/db hearts after exercise. In conclusion, while GATA4 expression is increased following exercise, not all structural and cardioprotective genes are expressed, suggesting other transcription factors may be involved in this regulation. Regardless of this effect, the positive effect of exercise training on key protective genes is evident 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 ß-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 ß-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.
