Remodeling of outward K+ currents in pressure-overload heart failure

Yanggan Wang, Jun Cheng, Guohua Chen, Farhana Rob, R. Haris Naseem, Lan Nguyen, Janet L. Johnstone, Joseph A Hill

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Objectives: Outward K+ currents are critical determinants of action potential repolarization and the site of action of a number of electrophysiologically active drugs. Further, expression and processing of the channels underlying these currents is altered in heart disease. Here, we investigated the native transmural gradient of outward K+ currents in murine left ventricle (LV) and delineated disease-related remodeling of these currents in heart failure (HF). Methods: Pressure-overload heart failure was induced in mice by thoracic aortic constriction. Outward K+ currents were recorded using the whole-cell patch clamp technique in acutely dissociated ventricular myocytes. Results: Unambiguous gradients of outward K+ current density and Kv4.2 protein abundance were observed across the wall of the LV, with significantly larger current density and protein levels in subepicardial (SEP) myocytes, compared with subendocardial (SEN) myocytes. Voltage dependences of current activation and inactivation were similar in SEP and SEN myocytes. In failing LV, however, outward K+ current density was significantly decreased in SEP but not in SEN cells leading to elimination of the native transmural gradient. In failing LV, the voltage dependences of K+ current activation and inactivation were not altered. However, current inactivation (decay) was significantly accelerated and recovery from inactivation was significantly slowed. Consistent with this, Western blot analysis revealed a decrease in KChIP2 protein abundance in failing LV. Conclusions: This is the first report of HF-related remodeling of outward K + currents in murine LV. Similar to humans, disease-related remodeling occurs differentially across the murine ventricular wall, leading to loss of the native gradient of repolarization. Together with slowed recovery from inactivation, these alterations likely promote abnormal impulse conduction, a major proarrhythmic mechanism.

Original languageEnglish (US)
Pages (from-to)869-875
Number of pages7
JournalJournal of Cardiovascular Electrophysiology
Volume18
Issue number8
DOIs
StatePublished - Aug 2007

Fingerprint

Heart Ventricles
Heart Failure
Pressure
Muscle Cells
Kv Channel-Interacting Proteins
Patch-Clamp Techniques
Constriction
Action Potentials
Heart Diseases
Proteins
Thorax
Western Blotting
Pharmaceutical Preparations

Keywords

  • Heart failure
  • Ion channels
  • Potassium channel
  • Transient outward current

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology

Cite this

Remodeling of outward K+ currents in pressure-overload heart failure. / Wang, Yanggan; Cheng, Jun; Chen, Guohua; Rob, Farhana; Haris Naseem, R.; Nguyen, Lan; Johnstone, Janet L.; Hill, Joseph A.

In: Journal of Cardiovascular Electrophysiology, Vol. 18, No. 8, 08.2007, p. 869-875.

Research output: Contribution to journalArticle

Wang, Y, Cheng, J, Chen, G, Rob, F, Haris Naseem, R, Nguyen, L, Johnstone, JL & Hill, JA 2007, 'Remodeling of outward K+ currents in pressure-overload heart failure', Journal of Cardiovascular Electrophysiology, vol. 18, no. 8, pp. 869-875. https://doi.org/10.1111/j.1540-8167.2007.00864.x
Wang, Yanggan ; Cheng, Jun ; Chen, Guohua ; Rob, Farhana ; Haris Naseem, R. ; Nguyen, Lan ; Johnstone, Janet L. ; Hill, Joseph A. / Remodeling of outward K+ currents in pressure-overload heart failure. In: Journal of Cardiovascular Electrophysiology. 2007 ; Vol. 18, No. 8. pp. 869-875.
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AU - Cheng, Jun

AU - Chen, Guohua

AU - Rob, Farhana

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AU - Nguyen, Lan

AU - Johnstone, Janet L.

AU - Hill, Joseph A

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AB - Objectives: Outward K+ currents are critical determinants of action potential repolarization and the site of action of a number of electrophysiologically active drugs. Further, expression and processing of the channels underlying these currents is altered in heart disease. Here, we investigated the native transmural gradient of outward K+ currents in murine left ventricle (LV) and delineated disease-related remodeling of these currents in heart failure (HF). Methods: Pressure-overload heart failure was induced in mice by thoracic aortic constriction. Outward K+ currents were recorded using the whole-cell patch clamp technique in acutely dissociated ventricular myocytes. Results: Unambiguous gradients of outward K+ current density and Kv4.2 protein abundance were observed across the wall of the LV, with significantly larger current density and protein levels in subepicardial (SEP) myocytes, compared with subendocardial (SEN) myocytes. Voltage dependences of current activation and inactivation were similar in SEP and SEN myocytes. In failing LV, however, outward K+ current density was significantly decreased in SEP but not in SEN cells leading to elimination of the native transmural gradient. In failing LV, the voltage dependences of K+ current activation and inactivation were not altered. However, current inactivation (decay) was significantly accelerated and recovery from inactivation was significantly slowed. Consistent with this, Western blot analysis revealed a decrease in KChIP2 protein abundance in failing LV. Conclusions: This is the first report of HF-related remodeling of outward K + currents in murine LV. Similar to humans, disease-related remodeling occurs differentially across the murine ventricular wall, leading to loss of the native gradient of repolarization. Together with slowed recovery from inactivation, these alterations likely promote abnormal impulse conduction, a major proarrhythmic mechanism.

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KW - Potassium channel

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