Electrical remodeling of the diseased heart is characterized by profound changes in ion channel activity that contributes to contractile dysfunction and arrhythmic sudden death in heart failure patients. Our laboratory has + shown that oxidative stress underlies K channel remodeling in the rat heart with chronic infarction through redox-mediated mechanisms. Preliminary data further suggest that these mechanisms involve thiol oxidoreductase systems whose primary biological role is to protect cellular proteins from oxidative damage. The thioredoxin system, which is composed of thioredoxin, thioredoxin reductase and NADPH, is a major oxidoreductase network affecting cardiovascular function, but its role in regulating ion channels is not known. The present project will fill this gap in knowledge by testing the central hypothesis that remodeling of K+ channels in the failing heart involves impairment of the thioredoxin system that normally functions as a repair mechanism to protect cell proteins from oxidative damage.
The specific aims of the proposed studies are to: 1) define the electrophysiological function of the thioredoxin system in the ventricle, and 2) identify cellular mechanisms that regulate the thioredoxin system and determine their impact on K+ channel remodeling. Isolated ventricular myocytes from rat and mouse hearts with chronic myocardial infarction will be used as the primary experimental tool to study redox-related factors controlling pathogenic electrical remodeling. Studies will include a comparison of the impact of chronic infarction on transgenic mice with cardiac-specific depletion or over-expression of thioredoxin. The primary focus of our experiments will be on mechanisms involved in the remodeling of K+ channels underlying the transient outward current, Ito, which will be examined by the patch-clamp technique. Electrophysiological data will be correlated with molecular studies of K+ channel a-subunit expression, as well as biochemical and molecular analyses of the activity/expression of thioredoxin and its up-stream regulator, thioredoxin reductase. This project will explore fundamental, biological processes that regulate cardiac ion channel activity and establish a basic framework for therapies aimed at preventing or reversing pathogenic electrical remodeling in the failing heart. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066446-06
Application #
7215250
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2000-09-30
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
6
Fiscal Year
2007
Total Cost
$285,474
Indirect Cost
Name
University of Nebraska Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
168559177
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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