Molecular role of GATA binding protein 4 (GATA-4) in hyperglycemia-induced reduction of cardiac contractility

Department of Medical Research, Chi-Mei Medical Center, No, 901 Chon-Hwa Road, Yong Kang, Tainan City, Taiwan.
Cardiovascular Diabetology (Impact Factor: 4.02). 06/2011; 10(1):57. DOI: 10.1186/1475-2840-10-57
Source: PubMed


Diabetic 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).
Streptozotocin-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.
Cardiac 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.
Hyperglycemia 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.

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    • "For the induction of diabetes, fasting rats were anesthetized with sodium pentobarbital (30 mg/kg) and intravenously injected with STZ (60 mg/kg freshly dissolved in sterile, non-pyrogenic 0.9% NaCl solution in a volume of 1 mL/kg body weight [35]) through the tail vein after a 72-h fast [36]. Two weeks after the STZ injection, the animals were considered to have type 1 diabetes if the plasma glucose level was > 350 mg/dL and diabetic features such as polyuria, polydipsia, and hyperphagia were observed [37].Four weeks after the STZ induction, the animals were divided into three groups: age-matched non-diabetic control animals; STZ-diabetic rats administered vehicle (distilled water) for 4 weeks; and, STZ-diabetic rats administered CAPA (1 mg/kg/day) for 4 weeks (Figure 2, panel 2). "
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    ABSTRACT: Background Caffeic acid phenethyl ester (CAPE) has been shown to protect the heart against ischemia/reperfusion (I/R) injury by various mechanisms including its antioxidant effect. In this study, we evaluated the protective effects of a CAPE analog with more structural stability in plasma, caffeic acid phenethyl amide (CAPA), on I/R injury in streptozotocin (STZ)-induced type 1 diabetic rats. Methods Type 1 diabetes mellitus was induced in Sprague–Dawley rats by a single intravenous injection of 60 mg/kg STZ. To produce the I/R injury, the left anterior descending coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. CAPA was pretreated intraperitoneally 30 minutes before reperfusion. An analog devoid of the antioxidant property of CAPA, dimethoxyl CAPA (dmCAPA), and a nitric oxide synthase (NOS) inhibitor (Nω-nitro-l-arginine methyl ester [l-NAME]) were used to evaluate the mechanism involved in the reduction of the infarct size following CAPA-treatment. Finally, the cardioprotective effect of chronic treatment of CAPA was analyzed in diabetic rats. Results Compared to the control group, CAPA administration (3 and 15 mg/kg) significantly reduced the myocardial infarct size after I/R, while dmCAPA (15 mg/kg) had no cardioprotective effect. Interestingly, pretreatment with a NOS inhibitor, (l-NAME, 3 mg/kg) eliminated the effect of CAPA on myocardial infarction. Additionally, a 4-week CAPA treatment (1 mg/kg, orally, once daily) started 4 weeks after STZ-induction could effectively decrease the infarct size and ameliorate the cardiac dysfunction by pressure-volume loop analysis in STZ-induced diabetic animals. Conclusions CAPA, which is structurally similar to CAPE, exerts cardioprotective activity in I/R injury through its antioxidant property and by preserving nitric oxide levels. On the other hand, chronic CAPA treatment could also ameliorate cardiac dysfunction in diabetic animals.
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    • "Cardiac phospho-SMAD2 and phospho-SMAD3 were also increased in high-fructose-fed diabetic rats [69] and STZ-induced diabetic rats [70]. One study found an increase in phosphorylated GATA4 in STZ-induced diabetic rat hearts [71]. "
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    PLoS ONE 03/2014; 9(3):e92903. DOI:10.1371/journal.pone.0092903 · 3.23 Impact Factor
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    • "siRNA was transfected to cardiomyocytes to knockdown PERK, IRE1 and ATF6 expression respectively. It has been documented that high glucose concentrations could increase the intracellular ROS production in myocyte, causing and promoting DCM [66,67]. In this study, as shown in Figure 6, we also found that high glucose concentration (33 mM) caused an increased generation of ROS production in both cultured wild type and the three ER sensors knockdown cardiomyocytes. "
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