UP-REGULATION OF K+ CHANNELS IN THE REMODELED VENTRICLE

  • Rozanski, George J, (PI)

Project: Research project

Description

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.
StatusFinished
Effective start/end date9/30/003/31/11

Funding

  • National Institutes of Health: $245,642.00
  • National Institutes of Health: $285,474.00
  • National Institutes of Health: $285,474.00
  • National Institutes of Health: $246,046.00
  • National Institutes of Health: $319,000.00
  • National Institutes of Health: $246,433.00
  • National Institutes of Health: $285,474.00
  • National Institutes of Health: $343,459.00

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Atrial Remodeling
Oxidation-Reduction
Thioredoxins
Glutathione
Up-Regulation
Muscle Cells
Ion Channels
Thioredoxin-Disulfide Reductase
Cardiac Arrhythmias
Patch-Clamp Techniques
Heart Failure
Infarction
Down-Regulation
Proteins
Biological Phenomena
Myocardial Infarction
Immunoblotting
Action Potentials
Sudden Death
Buffers

ASJC

  • Medicine(all)