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J. Biol. Chem., Vol. 282, Issue 30, 21945-21952, July 27, 2007

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Diminished GATA4 Protein Levels Contribute to Hyperglycemia-induced Cardiomyocyte Injury^*

Satoru Kobayashi¹², Kai Mao¹, Hanqiao Zheng, Xuejun Wang, Cam Patterson, Timothy D. O'Connell, and Qiangrong Liang³

From the Cardiovascular Research Institute, Sanford Research, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota 57105 and Carolina Cardiovascular Biology Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599

Hyperglycemia is an independent risk factor for diabetic heart failure. However, the mechanisms that mediate hyperglycemia-induced cardiac damage remain poorly understood. The transcription factor GATA4 is essential for cardiac homeostasis, and its protein levels are dramatically reduced in the heart in response to diverse pathologic stresses. In this study, we investigated if hyperglycemia affects GATA4 expression in cardiomyocytes and if enhancing GATA4 signaling could attenuate hyperglycemia-induced cardiomyocyte injury. In cultured rat cardiomyocytes, high glucose (HG, 25 or 40 mM) markedly reduced GATA4 protein levels as compared with normal glucose (NG, 5.5 mM). Equal amount of mannitol did not affect GATA4 protein expression (NG, 100 ± 12%; mannitol, 97 ± 8%, versus HG, 43 ± 16%, p < 0.05). The GATA4 mRNA content, either steady-state or polysome-associated, remained unchanged. HG-induced GATA4 reduction was reversed by MG262, a specific proteasome inhibitor. HG did not activate the ubiquitin proteasome system (UPS) in cardiomyocytes as indicated by a UPS reporter, nor did it increase the peptidase activities or protein expression of the proteasomal subunits. However, the mRNA levels of ubiquitin-protein isopeptide ligase (E3) carboxyl terminus of Hsp70-interacting protein (CHIP) were markedly increased in HG-treated cardiomyocytes. CHIP overexpression promoted GATA4 protein degradation, whereas small interfering RNA-mediated CHIP knockdown prevented HG-induced GATA4 depletion. Moreover, overexpression of GATA4 blocked HG-induced cardiomyocyte death. Also, GATA4 protein levels were diminished in the hearts of streptozotocin and db/db diabetic mice (44 ± 7% and 67 ± 13% of control, p < 0.05), which correlated with increased CHIP mRNA abundance. In summary, increased GATA4 protein degradation may be an important mechanism that contributes to hyperglycemic cardiotoxicity.

Received for publication, April 11, 2007 , and in revised form, May 24, 2007.

^* This work was supported in part by Grant P20 RR-017662 (Project 3) from the National Center for Research Resources (to Q. L.) of the National Institutes of Health and American Heart Association Scientist Development Grant 0435308N (to Q. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Supported by an American Heart Association postdoctoral fellowship.

³ To whom correspondence should be addressed. Tel.: 605-328-1308; Fax: 605-328-1301; E-mail: qliang{at}usd.edu.

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