- 作者：Cé ; line Marionneau ; Franck Aimond ; Sylvain Brunet ; Noriko Niwa ; Brian Finck ; Daniel P. Kelly ; Jeanne M. Nerbonne
- 关键词：Fatty acid metabolism ; Glucose metabolism ; Diabetes ; Diabetic cardiomyopathy ; Cardiac remodeling ; Kv currents ; Repolarization ; Arrhythmias
- 刊名：Journal of Molecular and Cellular Cardiology
- 出版年：2008
- 期刊代码：171_00222828
- 类别：bio
- 出版时间：June 2008
- 卷：44
- 期：6
- 页码：1002-1015
- 文件大小：828 K
摘要
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-PPAR
) with cardiac-specific overexpression of the peroxisome proliferator-activated receptor (PPAR), 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-PPAR 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-PPAR, 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-PPAR, compared with WT, ventricles. Western blot analyses revealed that expression of the Kv accessory protein, KChIP2, is also reduced in MHC-PPAR 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-PPAR and WT ventricles are not significantly different. The molecular mechanisms underlying Ito,f and Iss remodeling in MHC-PPAR ventricular myocytes, therefore, are distinct.
) with cardiac-specific overexpression of the peroxisome proliferator-activated receptor (PPAR), 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-PPAR 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-PPAR, 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-PPAR, compared with WT, ventricles. Western blot analyses revealed that expression of the Kv accessory protein, KChIP2, is also reduced in MHC-PPAR 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-PPAR and WT ventricles are not significantly different. The molecular mechanisms underlying Ito,f and Iss remodeling in MHC-PPAR ventricular myocytes, therefore, are distinct.© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |