Electrical remodeling of the heart predisposes to arrhythmias which largely account for the high incidence of morbidity and mortality in patients with chronic cardiac disorders. It is postulated that down-regulation of K+ currents, particularly the transient outward current, Ito, contributes to this increased risk of arrhythmogenesis via repolarization abnormalities. This project will explore the endogenous redox buffer glutathione as an antiarrhythmic intermediate that up-regulates Ito channel activity in the electrically remodeled ventricle. Our studies will test the central hypothesis that down-regulation of Ito in the remodeled ventricle is mediated by a reversible decrease in myocyte redox state by addressing three specific aims: (1) to determine the impact of glutathione precursors on redox state and Ito in myocytes from the remodeled ventricle, (2) to determine if metabolic control of Ito via glucose utilization is mediated by alterations in glutathione, and (3) to determine if glutathione modulators increase expression of Ito channels in the remodeled ventricle. We will conduct studies on isolated ventricular myocytes from rat hearts undergoing remodeling due to chronic myocardial infarction or hypertension. The patch-clamp technique will be used to record action potentials, as well as whole-cell and single channel currents in myocytes treated with pharmacologic modulators of glutathione. Changes in glutathione redox state, measured by an HPLC- fluorescent labeling technique, will be correlated with electrophysiological properties and the expression of the major channel isoforms underlying Ito, Kv4.2 and Kv4.3, by immunoblotting of channel protein. Changes in steady- state levels of channel mRNA will also be determined by semi-quantitative RT-PCR. We propose that these experiments will identify endogenous pathways that may be effective therapeutic targets to correct or prevent arrhythmias in the remodeled heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066446-03
Application #
6527719
Study Section
Special Emphasis Panel (ZHL1-CSR-O (S1))
Program Officer
Lathrop, David A
Project Start
2000-09-30
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$246,046
Indirect Cost
Name
University of Nebraska Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Zheng, Ming-Qi; Li, Xun; Tang, Kang et al. (2013) Pyruvate restores ?-adrenergic sensitivity of L-type Ca(2+) channels in failing rat heart: role of protein phosphatase. Am J Physiol Heart Circ Physiol 304:H1352-60
Tang, Kang; Li, Xun; Zheng, Ming-Qi et al. (2011) Role of apoptosis signal-regulating kinase-1-c-Jun NH2-terminal kinase-p38 signaling in voltage-gated K+ channel remodeling of the failing heart: regulation by thioredoxin. Antioxid Redox Signal 14:25-35
Babai, Norbert; Kanevsky, Nataly; Dascal, Nathan et al. (2010) Anion-sensitive regions of L-type CaV1.2 calcium channels expressed in HEK293 cells. PLoS One 5:e8602
Shao, Chun-Hong; Rozanski, George J; Nagai, Ryoji et al. (2010) Carbonylation of myosin heavy chains in rat heart during diabetes. Biochem Pharmacol 80:205-17
Li, Shumin; Zheng, Ming-Qi; Rozanski, George J (2009) Glutathione homeostasis in ventricular myocytes from rat hearts with chronic myocardial infarction. Exp Physiol 94:815-24
Shao, Chun-Hong; Wehrens, Xander H T; Wyatt, Todd A et al. (2009) Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation. J Appl Physiol (1985) 106:1280-92
Zheng, Ming-Qi; Tang, Kang; Zimmerman, Matthew C et al. (2009) Role of gamma-glutamyl transpeptidase in redox regulation of K+ channel remodeling in postmyocardial infarction rat hearts. Am J Physiol Cell Physiol 297:C253-62
Bidasee, Keshore R; Zheng, Hong; Shao, Chun-Hong et al. (2008) Exercise training initiated after the onset of diabetes preserves myocardial function: effects on expression of beta-adrenoceptors. J Appl Physiol 105:907-14
Li, Xun; Tang, Kang; Xie, Bin et al. (2008) Regulation of Kv4 channel expression in failing rat heart by the thioredoxin system. Am J Physiol Heart Circ Physiol 295:H416-24
Liang, Huixu; Li, Xun; Li, Shumin et al. (2008) Oxidoreductase regulation of Kv currents in rat ventricle. J Mol Cell Cardiol 44:1062-71

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