Altered K⁺ channel gene expression in diabetic rat ventricle: isoform switching between Kv4.2 and Kv1.4

Abstract

Expression of voltage-gated K(+) channels encoding the K(+) independent transient outward current in the streptozocin-induced diabetic (DM) rat ventricle was studied to determine the basis for slowed cardiac repolarization in diabetes mellitus. Although hypertrophy was not detected in diabetic rats at 12 wk after streptozocin treatment, ventricular Kv4.2 mRNA levels decreased 41% relative to nondiabetic controls. Kv1.4 mRNA levels increased 179% relative to controls, whereas Kv4.3 mRNA levels were unaffected. Immunohistochemistry and Western blot analysis of the diabetic heart showed that the density of the Kv4.2 protein decreased, whereas Kv1.4 protein increased. Thus isoform switching from Kv4.2 to Kv1.4 is most likely the mechanism underlying the slower kinetics of transient outward K(+) current observed in the diabetic ventricle. Brain Kv1.4, Kv4.2, or Kv4.3 mRNA levels were unaffected by diabetes. Myosin heavy chain (MHC) gene expression was altered with a 32% decrease in alpha-MHC mRNA and a 259% increase in beta-MHC mRNA levels in diabetic ventricle. Low-dose insulin-like growth factor-II (IGF-II) treatment during the last 6 of the 12 wk of diabetes (DM + IGF) protected against these changes in MHC mRNAs despite continued hyperglycemia and body weight loss. IGF-II treatment did not change K(+) channel mRNA levels in DM or control rat ventricles. Thus IGF treatment may prevent some, but not all, biochemical abnormalities in the diabetic heart.

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

“…Reductions of the K + channel subunit, Kv4.2, interacting protein KChIP2, and Ca 2+ channel α‐1C subunit have been proposed as molecular substrates for the decreased Kv currents and I CaL in myocytes from rodent models of diabetes 43, 45, 46, 47, 57, 59. Our electrophysiological data support the possibility that similar alterations occur in the STZ‐hyperglycemic mouse model employed here.…”

A Case of Hypothyroidism with Brugada Electrocardiographic Waveforms

“…[18]. These reports suggest that I to , especially its rapidly inactivated component, is suppressed in diabetic states.…”

Comparison of the effects of antiarrhythmic drugs flecainide and verapamil on fKv1.4ΔN channel currents in Xenopus oocytes

“…Although the antiarrhythmic efficacy of flecainide has usually been ascribed to its suppression of sodium channels, our findings suggest that the blockade of fKv1.4ΔN channels may also contribute to the cardiac effects of flecainide. The Kv1.4 channel, which conducts I to , contributes to phase 1 and the early part of phase 2 of the cardiac action potential and plays an important role in the repolarization of cardiac myocytes [4][5][6][7] . Flecainide and verapamil share an ability to inhibit the fKv1.4ΔN currents and increase c-type inactivation.…”

“…This channel conducts transient outward potassium currents (I to ). Kv1.4 expression in the mammalian endocardium is upregulated during hypertrophy and heart failure [4][5][6][7] , and this channel plays an important role in the repolarization of cardiac myocytes. The inactivation of Kv1.4 occurs through two distinct mechanisms: fast N-type inactivation and slow C-type inactivation [8] .…”