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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2011

Open Access 01-12-2011 | Original investigation

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

Authors: Po-Ming Ku, Li-Jen Chen, Jia-ru Liang, Kai-Chun Cheng, Yin-Xiao Li, Juei-Tang Cheng

Published in: Cardiovascular Diabetology | Issue 1/2011

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Abstract

Background

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).

Methods

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.

Results

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.

Conclusions

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.
Appendix
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Literature
1.
Kannel WB, Hjortland M, Castelli WP: Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974, 34: 29-34.CrossRefPubMed
2.
Kannel WB, McGee DL: Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979, 241: 2035-2038.CrossRefPubMed
3.
Malmberg K, Ryden L: Myocardial infarction in patients with diabetes mellitus. Eur Heart J. 1988, 9: 259-264.PubMed
4.
Herlitz J, Malmberg K, Karlson BW, Ryden L, Hjalmarson A: Mortality and morbidity during a five-year follow-up of diabetics with myocardial infarction. Acta Med Scand. 1988, 224: 31-38.CrossRefPubMed
5.
Poornima IG, Parikh P, Shannon RP: Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res. 2006, 98: 596-605.CrossRefPubMed
6.
Frede S, Stockmann C, Freitag P, Fandrey J: Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB. Biochem J. 2006, 396: 517-527.PubMedCentralCrossRefPubMed
7.
Pieske BM, Kraigher-Krainer E: Diabetes mellitus, natriuretic peptide axis dysregulation, and diabetic cardiomyopathy. Eur J Heart Fail. 2010, 12: 898-900.CrossRefPubMed
8.
9.
10.
Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ: Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes. 2002, 51: 1938-1948.CrossRefPubMed
11.
Wold LE, Ren J: Streptozotocin directly impairs cardiac contractile function in isolated ventricular myocytes via a p38 map kinase-dependent oxidative stress mechanism. Biochem Biophys Res Commun. 2004, 318: 1066-1071.CrossRefPubMed
12.
Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH: Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA. 2000, 97: 1784-1789.PubMedCentralCrossRefPubMed
13.
Murakami C, Nakamura S, Kobayashi M, Maeda K, Irie W, Wada B, Hayashi M, Sasaki C, Nakamaru N, Furukawa M, Kurihara K: Analysis of the sarcomere protein gene mutation on cardiomyopathy - Mutations in the cardiac troponin I gene. Leg Med (Tokyo). 2010, 12: 280-283.CrossRef
14.
Du J, Nan C, Huang JJ, Zhang C, Liu J, Jia P, Abers M, Huang XP: Functional characterization of mouse fetal TnI gene promoters in myocardial cells. J Biomed Sci. 2008, 15: 605-613.CrossRefPubMed
15.
Liang Q, Wiese RJ, Bueno OF, Dai YS, Markham BE, Molkentin JD: The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes. Mol Cell Biol. 2001, 21: 7460-7469.PubMedCentralCrossRefPubMed
16.
Charron F, Tsimiklis G, Arcand M, Robitaille L, Liang Q, Molkentin JD, Meloche S, Nemer M: Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA. Genes Dev. 2001, 15: 2702-2719.PubMedCentralCrossRefPubMed
17.
Ueyama T, Kawashima S, Sakoda T, Rikitake Y, Ishida T, Kawai M, Yamashita T, Ishido S, Hotta H, Yokoyama M: Requirement of activation of the extracellular signal-regulated kinase cascade in myocardial cell hypertrophy. J Mol Cell Cardiol. 2000, 32: 947-960.CrossRefPubMed
18.
Takeishi Y, Abe J, Lee JD, Kawakatsu H, Walsh RA, Berk BC: Differential regulation of p90 ribosomal S6 kinase and big mitogen-activated protein kinase 1 by ischemia/reperfusion and oxidative stress in perfused guinea pig hearts. Circ Res. 1999, 85: 1164-1172.CrossRefPubMed
19.
Babu GJ, Lalli MJ, Sussman MA, Sadoshima J, Periasamy M: Phosphorylation of elk-1 by MEK/ERK pathway is necessary for c-fos gene activation during cardiac myocyte hypertrophy. J Mol Cell Cardiol. 2000, 32: 1447-1457.CrossRefPubMed
20.
Clerk A, Bogoyevitch MA, Anderson MB, Sugden PH: Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine and subsequent stimulation of p42 and p44 mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts. J Biol Chem. 1994, 269: 32848-32857.PubMed
21.
Naito Z, Takashi E, Xu G, Ishiwata T, Teduka K, Yokoyama M, Yamada N, Sugisaki Y, Asano G: Different influences of hyperglycemic duration on phosphorylated extracellular signal-regulated kinase 1/2 in rat heart. Exp Mol Pathol. 2003, 74: 23-32.CrossRefPubMed
22.
Antos CL, McKinsey TA, Frey N, Kutschke W, McAnally J, Shelton JM, Richardson JA, Hill JA, Olson EN: Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivo. Proc Natl Acad Sci USA. 2002, 99: 907-912.PubMedCentralCrossRefPubMed
23.
Morisco C, Seta K, Hardt SE, Lee Y, Vatner SF, Sadoshima J: Glycogen synthase kinase 3beta regulates GATA4 in cardiac myocytes. J Biol Chem. 2001, 276: 28586-28597.CrossRefPubMed
24.
Fan SC, Yu BC, Chen ZC, Chen LJ, Chung HH, Cheng JT: The decreased expression of peroxisome proliferator-activated receptors delta (PPARdelta) is reversed by digoxin in the heart of diabetic rats. Horm Metab Res. 2010, 42: 637-642.CrossRefPubMed
25.
Yu BC, Chang CK, Ou HY, Cheng KC, Cheng JT: Decrease of peroxisome proliferator-activated receptor delta expression in cardiomyopathy of streptozotocin-induced diabetic rats. Cardiovasc Res. 2008, 80: 78-87.CrossRefPubMed
26.
Landau D, Chayat C, Zucker N, Golomb E, Yagil C, Yagil Y, Segev Y: Early blood pressure-independent cardiac changes in diabetic rats. J Endocrinol. 2008, 197: 75-83.CrossRefPubMed
27.
Liu IM, Tzeng TF, Tsai CC, Lai TY, Chang CT, Cheng JT: Increase in adenosine A1 receptor gene expression in the liver of streptozotocin-induced diabetic rats. Diabetes Metab Res Rev. 2003, 19: 209-215.CrossRefPubMed
28.
Planavila A, Rodriguez-Calvo R, Jove M, Michalik L, Wahli W, Laguna JC, Vazquez-Carrera M: Peroxisome proliferator-activated receptor beta/delta activation inhibits hypertrophy in neonatal rat cardiomyocytes. Cardiovasc Res. 2005, 65: 832-841.CrossRefPubMed
29.
Hsieh TJ, Zhang SL, Filep JG, Tang SS, Ingelfinger JR, Chan JS: High glucose stimulates angiotensinogen gene expression via reactive oxygen species generation in rat kidney proximal tubular cells. Endocrinology. 2002, 143: 2975-2985.CrossRefPubMed
30.
Tiwari M, Lopez-Cruzan M, Morgan WW, Herman B: Loss of caspase-2-dependent apoptosis induces autophagy after mitochondrial oxidative stress in primary cultures of young adult cortical neurons. J Biol Chem. 2011, 286: 8493-8506.PubMedCentralCrossRefPubMed
31.
Chen JS, Lee HS, Jin JS, Chen A, Lin SH, Ka SM, Lin YF: Attenuation of mouse mesangial cell contractility by high glucose and mannitol: involvement of protein kinase C and focal adhesion kinase. J Biomed Sci. 2004, 11: 142-151.CrossRefPubMed
32.
Muniyappa R, Montagnani M, Koh KK, Quon MJ: Cardiovascular actions of insulin. Endocr Rev. 2007, 28: 463-491.CrossRefPubMed
33.
Lamirault G, Gaborit N, Le Meur N, Chevalier C, Lande G, Demolombe S, Escande D, Nattel S, Leger JJ, Steenman M: Gene expression profile associated with chronic atrial fibrillation and underlying valvular heart disease in man. J Mol Cell Cardiol. 2006, 40: 173-184.CrossRefPubMed
34.
Grzeskowiak R, Witt H, Drungowski M, Thermann R, Hennig S, Perrot A, Osterziel KJ, Klingbiel D, Scheid S, Spang R, et al: Expression profiling of human idiopathic dilated cardiomyopathy. Cardiovasc Res. 2003, 59: 400-411.CrossRefPubMed
35.
Barrans JD, Allen PD, Stamatiou D, Dzau VJ, Liew CC: Global gene expression profiling of end-stage dilated cardiomyopathy using a human cardiovascular-based cDNA microarray. Am J Pathol. 2002, 160: 2035-2043.PubMedCentralCrossRefPubMed
36.
Ito H, Hirata Y, Hiroe M, Tsujino M, Adachi S, Takamoto T, Nitta M, Taniguchi K, Marumo F: Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res. 1991, 69: 209-215.CrossRefPubMed
37.
Ito H, Hiroe M, Hirata Y, Tsujino M, Adachi S, Shichiri M, Koike A, Nogami A, Marumo F: Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes. Circulation. 1993, 87: 1715-1721.CrossRefPubMed
38.
Malhotra A, Lopez MC, Nakouzi A: Troponin subunits contribute to altered myosin ATPase activity in diabetic cardiomyopathy. Mol Cell Biochem. 1995, 151: 165-172.CrossRefPubMed
39.
Malhotra A, Reich D, Nakouzi A, Sanghi V, Geenen DL, Buttrick PM: Experimental diabetes is associated with functional activation of protein kinase C epsilon and phosphorylation of troponin I in the heart, which are prevented by angiotensin II receptor blockade. Circ Res. 1997, 81: 1027-1033.CrossRefPubMed
40.
Cai L, Wang Y, Zhou G, Chen T, Song Y, Li X, Kang YJ: Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. J Am Coll Cardiol. 2006, 48: 1688-1697.CrossRefPubMed
41.
Liang Q, Carlson EC, Donthi RV, Kralik PM, Shen X, Epstein PN: Overexpression of metallothionein reduces diabetic cardiomyopathy. Diabetes. 2002, 51: 174-181.CrossRefPubMed
42.
Ye G, Metreveli NS, Donthi RV, Xia S, Xu M, Carlson EC, Epstein PN: Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. Diabetes. 2004, 53: 1336-1343.CrossRefPubMed
43.
Fiordaliso F, Bianchi R, Staszewsky L, Cuccovillo I, Doni M, Laragione T, Salio M, Savino C, Melucci S, Santangelo F, et al: Antioxidant treatment attenuates hyperglycemia-induced cardiomyocyte death in rats. J Mol Cell Cardiol. 2004, 37: 959-968.CrossRefPubMed
44.
45.
Murphy AM, Thompson WR, Peng LF, Jones L: Regulation of the rat cardiac troponin I gene by the transcription factor GATA-4. Biochem J. 1997, 322 (Pt 2): 393-401.PubMedCentralCrossRefPubMed
46.
Bhavsar PK, Dellow KA, Yacoub MH, Brand NJ, Barton PJ: Identification of cis-acting DNA elements required for expression of the human cardiac troponin I gene promoter. J Mol Cell Cardiol. 2000, 32: 95-108.CrossRefPubMed
47.
48.
Searls YM, Loganathan R, Smirnova IV, Stehno-Bittel L: Intracellular Ca2+ regulating proteins in vascular smooth muscle cells are altered with type 1 diabetes due to the direct effects of hyperglycemia. Cardiovasc Diabetol. 2010, 9: 8.PubMedCentralCrossRefPubMed
Metadata
Title
Molecular role of GATA binding protein 4 (GATA-4) in hyperglycemia-induced reduction of cardiac contractility
Authors
Po-Ming Ku
Li-Jen Chen
Jia-ru Liang
Kai-Chun Cheng
Yin-Xiao Li
Juei-Tang Cheng
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2011
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/1475-2840-10-57

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