title: Transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts.
abstract: The transient outward current (I(to)), an important contributor to transmural electrophysiological heterogeneity, is significantly remodelled in congestive heart failure (CHF). The molecular bases of transmural I(to) gradients and CHF-dependent ionic remodelling are incompletely understood. To elucidate these issues, we studied mRNA and protein expression of Kv4.3 and KChIP2, the principal alpha and beta subunits believed to form I(to), in epicardial and endocardial tissues and in isolated cardiomyocytes from control dogs and dogs with CHF induced by 240 beats min(-1) ventricular tachypacing. CHF decreased I(to) density in both epicardium and endocardium (by 73 and 55% at +60 mV, respectively), without a significant change in relative current density (endocardium/epicardium 0.11 control, 0.17 CHF). There were transmural gradients in mRNA expression of both Kv4.3 (endocardium/epicardium ratio 0.3 under control conditions) and KChIP2 (endocardium/epicardium ratio 0.2 control), which remained in the presence of CHF (Kv4.3 endocardium/epicardium ratio 0.4; KChIP2 0.4). There were qualitatively similar protein expression gradients in human and canine cardiac tissues and isolated canine cardiomyocytes; however, the KChIP2 gradient was only detectable with a highly selective monoclonal antibody and closely approximated the I(to) density gradient. Kv4.3 mRNA expression was reduced by CHF, but KChIP2 mRNA was not significantly changed. CHF decreased Kv4.3 protein expression in canine cardiac tissues and cardiomyocytes, as well as in terminally failing human heart tissue samples, but KChIP2 protein was not down-regulated in any of the corresponding sample sets. We conclude that both Kv4.3 and KChIP2 may contribute to epicardial-endocardial gradients in I(to), and that I(to) down-regulation in human and canine CHF appears due primarily to changes in Kv4.3.
authors.affiliation: Montreal Heart Institute Research Center, 5000 Belanger Street East, Montreal, Quebec H1T 1C8, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Zicha
authors.forename: Ling
authors.initials: L
authors.lastname: Xiao
authors.forename: Sara
authors.initials: S
authors.lastname: Stafford
authors.forename: Tae Joon
authors.initials: TJ
authors.lastname: Cha
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Andras
authors.initials: A
authors.lastname: Varro
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology; D004285:Dogs; D015536:Down-Regulation; D015870:Gene Expression / Q000502:physiology*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D051605:Kv Channel-Interacting Proteins; D009206:Myocardium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000096:biosynthesis* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051672:Shal Potassium Channels
chemical_list: D002135:Calcium-Binding Proteins; C497021:KCND3 protein, human; C496752:KCNIP2 protein, human; D051605:Kv Channel-Interacting Proteins; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D051672:Shal Potassium Channels