TY - JOUR
T1 - PPARα-mediated remodeling of repolarizing voltage-gated K+ (Kv) channels in a mouse model of metabolic cardiomyopathy
AU - Marionneau, Céline
AU - Aimond, Franck
AU - Brunet, Sylvain
AU - Niwa, Noriko
AU - Finck, Brian
AU - Kelly, Daniel P.
AU - Nerbonne, Jeanne M.
N1 - Funding Information:
The authors wish to thank Ms. Teresa Leone, Ms. Amy Coleman and Mr. Rick Wilson for screening and maintenance of animals and for expert technical assistance throughout the course of these studies. The authors also thank Dr. Thomas Steinberg for the generous gift of the anti-Cx45 antibody. Finally, the authors acknowledge the financial support provided by the National Institutes of Health (R01HL-034161 and R01HL-066388 to JMN and P50 HL077113 to DPK) and the Heartland Affiliate of the American Heart Association (Postdoctoral Fellowships to FA and CM).
PY - 2008/6
Y1 - 2008/6
N2 - 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.
AB - 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.
KW - Arrhythmias
KW - Cardiac remodeling
KW - Diabetes
KW - Diabetic cardiomyopathy
KW - Fatty acid metabolism
KW - Glucose metabolism
KW - Kv currents
KW - Repolarization
UR - http://www.scopus.com/inward/record.url?scp=44649129126&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2008.03.023
DO - 10.1016/j.yjmcc.2008.03.023
M3 - Article
C2 - 18482733
AN - SCOPUS:44649129126
VL - 44
SP - 1002
EP - 1015
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
IS - 6
ER -