Diminished GATA4 protein levels contribute to hyperglycemia-induced cardiomyocyte injury

Satoru Kobayashi, Kai Mao, Hanqiao Zheng, Xuejun Wang, Cam Patterson, Timothy D. O'Connell, Qiangrong Liang

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)21945-21952
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number30
DOIs
StatePublished - Jul 27 2007

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Cardiac Myocytes
Hyperglycemia
Wounds and Injuries
Proteins
Mannitol
Proteasome Endopeptidase Complex
Ubiquitin
Messenger RNA
Proteolysis
GATA4 Transcription Factor
Glucose
Proteasome Inhibitors
Ubiquitin-Protein Ligases
Polyribosomes
Degradation
Streptozocin
Small Interfering RNA
Homeostasis
Peptide Hydrolases
Heart Failure

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kobayashi, S., Mao, K., Zheng, H., Wang, X., Patterson, C., O'Connell, T. D., & Liang, Q. (2007). Diminished GATA4 protein levels contribute to hyperglycemia-induced cardiomyocyte injury. Journal of Biological Chemistry, 282(30), 21945-21952. https://doi.org/10.1074/jbc.M703048200

Diminished GATA4 protein levels contribute to hyperglycemia-induced cardiomyocyte injury. / Kobayashi, Satoru; Mao, Kai; Zheng, Hanqiao; Wang, Xuejun; Patterson, Cam; O'Connell, Timothy D.; Liang, Qiangrong.

In: Journal of Biological Chemistry, Vol. 282, No. 30, 27.07.2007, p. 21945-21952.

Research output: Contribution to journalArticle

Kobayashi, S, Mao, K, Zheng, H, Wang, X, Patterson, C, O'Connell, TD & Liang, Q 2007, 'Diminished GATA4 protein levels contribute to hyperglycemia-induced cardiomyocyte injury', Journal of Biological Chemistry, vol. 282, no. 30, pp. 21945-21952. https://doi.org/10.1074/jbc.M703048200
Kobayashi, Satoru ; Mao, Kai ; Zheng, Hanqiao ; Wang, Xuejun ; Patterson, Cam ; O'Connell, Timothy D. ; Liang, Qiangrong. / Diminished GATA4 protein levels contribute to hyperglycemia-induced cardiomyocyte injury. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 30. pp. 21945-21952.
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