Abstract
BackgroundDiabetic cardiomyopathy, a diabetes-specific complication, refers to a disorder that eventually leads to left ventricular hypertrophy in addition to diastolic and systolic dysfunction. In recent studies, hyperglycemia-induced reactive oxygen species (ROS) in cardiomyocytes have been linked to diabetic cardiomyopathy. GATA binding protein 4 (GATA-4) regulates the expression of many cardio-structural genes including cardiac troponin-I (cTnI).MethodsStreptozotocin-induced diabetic rats and H9c2 embryonic rat cardiomyocytes treated with a high concentration of glucose (a D-glucose concentration of 30 mM was used and cells were cultured for 24 hr) were used to examine the effect of hyperglycemia on GATA-4 accumulation in the nucleus. cTnI expression was found to be linked to cardiac tonic dysfunction, and we evaluated the expression levels of cTnI and GATA-4 by Western blot analysis.ResultsCardiac output was lowered in STZ-induced diabetic rats. In addition, higher expressions of cardiac troponin I (cTnI) and phosphorylated GATA-4 were identified in these rats by Western blotting. The changes were reversed by treatment with insulin or phlorizin after correction of the blood sugar level. In H9c2 cells, ROS production owing to the high glucose concentration increased the expression of cTnI and GATA-4 phosphorylation. However, hyperglycemia failed to increase the expression of cTnI when GATA-4 was silenced by small interfering RNA (siRNA) in H9c2 cells. Otherwise, activation of ERK is known to be a signal for phosphorylation of serine105 in GATA-4 to increase the DNA binding ability of this transcription factor. Moreover, GSK3β could directly interact with GATA-4 to cause GATA-4 to be exported from the nucleus. GATA-4 nuclear translocation and GSK3β ser9 phosphorylation were both elevated by a high glucose concentration in H9c2 cells. These changes were reversed by tiron (ROS scavenger), PD98059 (MEK/ERK inhibitor), or siRNA of GATA-4. Cell contractility measurement also indicated that the high glucose concentration decreased the contractility of H9c2 cells, and this was reduced by siRNA of GATA-4.ConclusionsHyperglycemia can cause systolic dysfunction and a higher expression of cTnI in cardiomyocytes through ROS, enhancing MEK/ERK-induced GATA-4 phosphorylation and accumulation in the cell nucleus.
Highlights
Diabetic cardiomyopathy, a diabetes-specific complication, refers to a disorder that eventually leads to left ventricular hypertrophy in addition to diastolic and systolic dysfunction
After treatment with insulin or phloridzin for 7 days, in parallel to the reversion of blood sugar, recovery of TnI protein expression or nucleus GATA binding protein 4 (GATA-4) phosphorylation was observed in the hearts of STZ-diabetic rats (Figure 1B, 1C)
The lucigenin assays showed that the generation of intracellular reactive oxygen species (ROS) in High glucose (HG)-treated neonatal rat cardiomyocytes and H9c2 cells was enhanced as compared with their control groups (Figure 2)
Summary
A diabetes-specific complication, refers to a disorder that eventually leads to left ventricular hypertrophy in addition to diastolic and systolic dysfunction. In recent studies, hyperglycemiainduced reactive oxygen species (ROS) in cardiomyocytes have been linked to diabetic cardiomyopathy. Many patients with CHF and hyperglycemic symptoms have accompanying abnormalities including obesity, dyslipidemia, and hypertension, which lead to structural and Diabetic cardiomyopathy appears to be related to hyperglycemia. Reactive oxygen species (ROS) generation has been detected in cells exposed to a high glucose concentration. Cell death such as apoptosis plays a critical role in cardiac pathogenesis. Hyperglycemia seems to be linked to apoptotic cell death in the myocardium in vivo. Hyperglycemia-induced myocardial apoptosis is mediated by ROS produced owing to the high glucose concentration [10,11,12]
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