Expression of cardiac GATA4 and downstream genes after exercise training in the db/db mouse

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 β-MHC, whereas mRNA expression of β-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 β-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.

► GATA4 regulates the transcription of key structural and cardioprotective genes.
► Synthesis of GATA4 is reduced in hearts from db/db mice, a model of type 2 diabetes mellitus.
► The effect of regular exercise, a recommended therapy in diabetes, on GATA4 expression and related genes was examined.
► Exercise increased GATA4 levels and genes for nitric oxide, myosin heavy chain, and vascular endothelial growth factor.
► A positive effect of exercise training on key protective genes occurs in hearts of db/db mice.