Molecular mechanisms underlying K+ current downregulation in canine tachycardia-induced heart failure

Fadi G. Akar, Richard C. Wu, George J. Juang, Yanli Tian, Mirka Burysek, Deborah DiSilvestre, Wei Xiong, Antonis A. Armoundas, Gordon F. Tomaselli

Research output: Contribution to journalArticle

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Abstract

Heart failure (HF) is characterized by marked prolongation of action potential duration and reduction in cellular repolarization reserve. These changes are caused in large part by HF-induced K+ current downregulation. Molecular mechanisms underlying these changes remain unclear. We determined whether downregulation of K+ currents in a canine model of tachycardia-induced HF is caused by altered expression of underlying K + channel α- and β-subunits encoding these currents. K+ channel subunit expression was quantified in normal and failing dogs at the mRNA and protein levels in epicardial (Epi), midmyocardial (Mid), and endocardial (Endo) layers of left ventricle. Analysis of mRNA and protein levels of candidate genes encoding the transient outward K+ current (Ito) revealed marked reductions in canine cKv4.3 expression in HF in Epi (44% mRNA, 39% protein), Mid (52% mRNA, 34% protein), and Endo (49% mRNA, 73% protein) layers and a paradoxical enhancement (41% Epi, 97% Mid, 113% Endo) in cKv1.4 protein levels, without significant changes in Kv channel-interacting protein cKChIP2 expression. Expression of cKir2.1, the gene underlying inward rectifier K+ current (IKl), was unaffected by HF at mRNA and protein levels despite significant reduction in IKl, whereas canine ether-à-go-go-related gene (cERG), which encodes the rapidly activating component of the delayed rectifier current (IK), exhibited increased protein expression. HF was not accompanied by significant changes in cKvLQT1 or cMinK mRNA and protein levels. These data indicate that 1) downregulation of Ito in HF is associated with decreased cKv4.3 and not cKv1.4 or cKChIP2, and 2) alterations in both the rapidly activating and slowly activating components of IK as well as IKl in nonischemic dilated cardiomyopathy are not caused by changes in either transcript or immunoreactive protein levels of relevant channel subunits, which suggests posttranslational modification of these currents by HF.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume288
Issue number6 57-6
DOIs
StatePublished - Jun 1 2005
Externally publishedYes

Fingerprint

Tachycardia
Canidae
Down-Regulation
Heart Failure
Messenger RNA
Proteins
Kv Channel-Interacting Proteins
Dilated Cardiomyopathy
Post Translational Protein Processing
Ether
Genes
Action Potentials
Heart Ventricles
Dogs
Gene Expression

Keywords

  • Inward rectifier
  • Myocardial infarction
  • Potassium current
  • Transient outward

ASJC Scopus subject areas

  • Physiology

Cite this

Molecular mechanisms underlying K+ current downregulation in canine tachycardia-induced heart failure. / Akar, Fadi G.; Wu, Richard C.; Juang, George J.; Tian, Yanli; Burysek, Mirka; DiSilvestre, Deborah; Xiong, Wei; Armoundas, Antonis A.; Tomaselli, Gordon F.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 288, No. 6 57-6, 01.06.2005.

Research output: Contribution to journalArticle

Akar, Fadi G. ; Wu, Richard C. ; Juang, George J. ; Tian, Yanli ; Burysek, Mirka ; DiSilvestre, Deborah ; Xiong, Wei ; Armoundas, Antonis A. ; Tomaselli, Gordon F. / Molecular mechanisms underlying K+ current downregulation in canine tachycardia-induced heart failure. In: American Journal of Physiology - Heart and Circulatory Physiology. 2005 ; Vol. 288, No. 6 57-6.
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AB - Heart failure (HF) is characterized by marked prolongation of action potential duration and reduction in cellular repolarization reserve. These changes are caused in large part by HF-induced K+ current downregulation. Molecular mechanisms underlying these changes remain unclear. We determined whether downregulation of K+ currents in a canine model of tachycardia-induced HF is caused by altered expression of underlying K + channel α- and β-subunits encoding these currents. K+ channel subunit expression was quantified in normal and failing dogs at the mRNA and protein levels in epicardial (Epi), midmyocardial (Mid), and endocardial (Endo) layers of left ventricle. Analysis of mRNA and protein levels of candidate genes encoding the transient outward K+ current (Ito) revealed marked reductions in canine cKv4.3 expression in HF in Epi (44% mRNA, 39% protein), Mid (52% mRNA, 34% protein), and Endo (49% mRNA, 73% protein) layers and a paradoxical enhancement (41% Epi, 97% Mid, 113% Endo) in cKv1.4 protein levels, without significant changes in Kv channel-interacting protein cKChIP2 expression. Expression of cKir2.1, the gene underlying inward rectifier K+ current (IKl), was unaffected by HF at mRNA and protein levels despite significant reduction in IKl, whereas canine ether-à-go-go-related gene (cERG), which encodes the rapidly activating component of the delayed rectifier current (IK), exhibited increased protein expression. HF was not accompanied by significant changes in cKvLQT1 or cMinK mRNA and protein levels. These data indicate that 1) downregulation of Ito in HF is associated with decreased cKv4.3 and not cKv1.4 or cKChIP2, and 2) alterations in both the rapidly activating and slowly activating components of IK as well as IKl in nonischemic dilated cardiomyopathy are not caused by changes in either transcript or immunoreactive protein levels of relevant channel subunits, which suggests posttranslational modification of these currents by HF.

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