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Role of gamma-glutamyl transpeptidase in redox regulation of K+ channel remodeling in postmyocardial infarction rat hearts.
Am J Physiol Cell Physiol. 2009 Aug; 297(2):C253-62.AJ

Abstract

gamma-Glutamyl transpeptidase (gamma-GT) is a key enzyme in GSH metabolism that regulates intracellular GSH levels in response to extracellular GSH (GSH(o)). The objective of this study was to identify the role of gamma-GT in reversing pathogenic K(+) channel remodeling in the diseased heart. Chronic ventricular dysfunction was induced in rats by myocardial infarction (MI), and studies were done after 6-8 wk. Biochemical assays of tissue extracts from post-MI hearts revealed significant increases in gamma-GT activity in left ventricle (47%) and septum (28%) compared with sham hearts, which paralleled increases in protein abundance and mRNA. Voltage-clamp studies of isolated left ventricular myocytes from post-MI hearts showed that downregulation of transient outward K(+) current (I(to)) was reversed after 4-5 h by 10 mmol/l GSH(o) or N-acetylcysteine (NAC(o)), and that the effect of GSH(o) but not NAC(o) was blocked by the gamma-GT inhibitors, acivicin or S-hexyl-GSH. Inhibition of gamma-glutamylcysteine synthetase by buthionine sulfoximine did not prevent upregulation of I(to) by GSH(o), suggesting that intracellular synthesis of GSH was not directly involved. However, pretreatment of post-MI myocytes with an SOD mimetic [manganese (III) tetrapyridylporphyrin] and catalase completely blocked recovery of I(to) by GSH(o). Confocal microscopy using the fluorogenic dye 2',7'-dichlorodihydrofluorescein diacetate confirmed that GSH(o) increased reactive oxygen species (ROS) generation by post-MI myocytes and to a lesser extent in myocytes from sham hearts. Furthermore, GSH(o)-mediated upregulation of I(to) was blocked by inhibitors of tyrosine kinase (genistein, lavendustin A, and AG1024) and thioredoxin reductase (auranofin and 13-cis-retinoic acid). These data suggest that GSH(o) elicits gamma-GT- and ROS-dependent transactivation of tyrosine kinase signaling that upregulates K(+) channel activity or expression via redox-mediated mechanisms. The signaling events stimulated by gamma-GT catalysis of GSH(o) may be a therapeutic target to reverse pathogenic electrical remodeling of the failing heart.

Authors+Show Affiliations

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19419996

Citation

Zheng, Ming-Qi, et al. "Role of Gamma-glutamyl Transpeptidase in Redox Regulation of K+ Channel Remodeling in Postmyocardial Infarction Rat Hearts." American Journal of Physiology. Cell Physiology, vol. 297, no. 2, 2009, pp. C253-62.
Zheng MQ, Tang K, Zimmerman MC, et al. Role of gamma-glutamyl transpeptidase in redox regulation of K+ channel remodeling in postmyocardial infarction rat hearts. Am J Physiol, Cell Physiol. 2009;297(2):C253-62.
Zheng, M. Q., Tang, K., Zimmerman, M. C., Liu, L., Xie, B., & Rozanski, G. J. (2009). Role of gamma-glutamyl transpeptidase in redox regulation of K+ channel remodeling in postmyocardial infarction rat hearts. American Journal of Physiology. Cell Physiology, 297(2), C253-62. https://doi.org/10.1152/ajpcell.00634.2008
Zheng MQ, et al. Role of Gamma-glutamyl Transpeptidase in Redox Regulation of K+ Channel Remodeling in Postmyocardial Infarction Rat Hearts. Am J Physiol, Cell Physiol. 2009;297(2):C253-62. PubMed PMID: 19419996.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of gamma-glutamyl transpeptidase in redox regulation of K+ channel remodeling in postmyocardial infarction rat hearts. AU - Zheng,Ming-Qi, AU - Tang,Kang, AU - Zimmerman,Matthew C, AU - Liu,Liping, AU - Xie,Bin, AU - Rozanski,George J, Y1 - 2009/05/06/ PY - 2009/5/8/entrez PY - 2009/5/8/pubmed PY - 2009/9/22/medline SP - C253 EP - 62 JF - American journal of physiology. Cell physiology JO - Am. J. Physiol., Cell Physiol. VL - 297 IS - 2 N2 - gamma-Glutamyl transpeptidase (gamma-GT) is a key enzyme in GSH metabolism that regulates intracellular GSH levels in response to extracellular GSH (GSH(o)). The objective of this study was to identify the role of gamma-GT in reversing pathogenic K(+) channel remodeling in the diseased heart. Chronic ventricular dysfunction was induced in rats by myocardial infarction (MI), and studies were done after 6-8 wk. Biochemical assays of tissue extracts from post-MI hearts revealed significant increases in gamma-GT activity in left ventricle (47%) and septum (28%) compared with sham hearts, which paralleled increases in protein abundance and mRNA. Voltage-clamp studies of isolated left ventricular myocytes from post-MI hearts showed that downregulation of transient outward K(+) current (I(to)) was reversed after 4-5 h by 10 mmol/l GSH(o) or N-acetylcysteine (NAC(o)), and that the effect of GSH(o) but not NAC(o) was blocked by the gamma-GT inhibitors, acivicin or S-hexyl-GSH. Inhibition of gamma-glutamylcysteine synthetase by buthionine sulfoximine did not prevent upregulation of I(to) by GSH(o), suggesting that intracellular synthesis of GSH was not directly involved. However, pretreatment of post-MI myocytes with an SOD mimetic [manganese (III) tetrapyridylporphyrin] and catalase completely blocked recovery of I(to) by GSH(o). Confocal microscopy using the fluorogenic dye 2',7'-dichlorodihydrofluorescein diacetate confirmed that GSH(o) increased reactive oxygen species (ROS) generation by post-MI myocytes and to a lesser extent in myocytes from sham hearts. Furthermore, GSH(o)-mediated upregulation of I(to) was blocked by inhibitors of tyrosine kinase (genistein, lavendustin A, and AG1024) and thioredoxin reductase (auranofin and 13-cis-retinoic acid). These data suggest that GSH(o) elicits gamma-GT- and ROS-dependent transactivation of tyrosine kinase signaling that upregulates K(+) channel activity or expression via redox-mediated mechanisms. The signaling events stimulated by gamma-GT catalysis of GSH(o) may be a therapeutic target to reverse pathogenic electrical remodeling of the failing heart. SN - 1522-1563 UR - https://www.unboundmedicine.com/medline/citation/19419996/Role_of_gamma_glutamyl_transpeptidase_in_redox_regulation_of_K+_channel_remodeling_in_postmyocardial_infarction_rat_hearts_ L2 - http://www.physiology.org/doi/full/10.1152/ajpcell.00634.2008?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -