Diabetes is associated with increased risk of diastolic dysfunction, heart failure, QT prolongation and rhythm disturbances independent of age, hypertension or coronary artery disease. Although these observations suggest electrical remodeling in the heart with diabetes, the relationship between the metabolic and the functional derangements is poorly understood. Exploiting a mouse model (MHC-PPARα) with cardiac-specific overexpression of the peroxisome proliferator-activated receptor α (PPARα), a key driver of diabetes-related lipid metabolic dysregulation, the experiments here were aimed at examining directly the link(s) between alterations in cardiac fatty acid metabolism and the functioning of repolarizing, voltage-gated K+ (Kv) channels. Electrophysiological experiments on left (LV) and right (RV) ventricular myocytes isolated from young (5-6 week) MHC-PPARα mice revealed marked K+ current remodeling: Ito,f densities are significantly (P < 0.01) lower, whereas Iss densities are significantly (P < 0.001) higher in MHC-PPARα, compared with age-matched wild type (WT), LV and RV myocytes. Consistent with the observed reductions in Ito,f density, expression of the KCND2 (Kv4.2) transcript is significantly (P < 0.001) lower in MHC-PPARα, compared with WT, ventricles. Western blot analyses revealed that expression of the Kv accessory protein, KChIP2, is also reduced in MHC-PPARα ventricles in parallel with the decrease in Kv4.2. Although the properties of the endogenous and the "augmented" Iss suggest a role(s) for two pore domain K+ channel (K2P) pore-forming subunits, the expression levels of KCNK2 (TREK1), KCNK3 (TASK1) and KCNK5 (TASK2) in MHC-PPARα and WT ventricles are not significantly different. The molecular mechanisms underlying Ito,f and Iss remodeling in MHC-PPARα ventricular myocytes, therefore, are distinct.

Original languageEnglish
Pages (from-to)1002-1015
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Issue number6
StatePublished - Jun 2008


  • Arrhythmias
  • Cardiac remodeling
  • Diabetes
  • Diabetic cardiomyopathy
  • Fatty acid metabolism
  • Glucose metabolism
  • Kv currents
  • Repolarization


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