PPARalpha-mediated remodeling of repolarizing voltage-gated K+ (Kv) channels in a mouse model of metabolic cardiomyopathy.
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-PPARalpha) with cardiac-specific overexpression of the peroxisome proliferator-activated receptor alpha (PPARalpha), 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-PPARalpha mice revealed marked K(+) current remodeling: I(to,f) densities are significantly (P<0.01) lower, whereas I(ss) densities are significantly (P<0.001) higher in MHC-PPARalpha, compared with age-matched wild type (WT), LV and RV myocytes. Consistent with the observed reductions in I(to,f) density, expression of the KCND2 (Kv4.2) transcript is significantly (P<0.001) lower in MHC-PPARalpha, compared with WT, ventricles. Western blot analyses revealed that expression of the Kv accessory protein, KChIP2, is also reduced in MHC-PPARalpha ventricles in parallel with the decrease in Kv4.2. Although the properties of the endogenous and the "augmented" I(ss) 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-PPARalpha and WT ventricles are not significantly different. The molecular mechanisms underlying I(to,f) and I(ss) remodeling in MHC-PPARalpha ventricular myocytes, therefore, are distinct.
Marionneau
Céline
C
Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110, USA.
Aimond
Franck
F
Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110, USA.
Brunet
Sylvain
S
Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110, USA.
Niwa
Noriko
N
Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110, USA.
Finck
Brian
B
Department of Internal Medicine, Washington University Medical School, St. Louis, MO 63110, USA.
Kelly
Daniel P
DP
Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110, USA; Department of Internal Medicine, Washington University Medical School, St. Louis, MO 63110, USA.
Nerbonne
Jeanne M
JM
Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110, USA. Electronic address: jnerbonne@wustl.edu.
D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D047493:PPAR alpha / Q000096:biosynthesis* / Q000235:genetics; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000235:genetics
D005227:Fatty Acids; C496755:Kcnip2 protein, mouse; D051605:Kv Channel-Interacting Proteins; D047493:PPAR alpha; D024642:Potassium Channels, Voltage-Gated; D011188:Potassium