title: Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease.
abstract: The mechanisms underlying chronic kidney disease (CKD)-associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Itocurrents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Itovia downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD.
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.|Cardiovascular Research Laboratory, China Medical University Hospital, Taichung, Taiwan.
authors.forename: An-Sheng
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Hua-Chen
authors.initials: HC
authors.lastname: Chan
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Ching-Hu
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Hsien-Yu
authors.initials: HY
authors.lastname: Peng
authors.affiliation: Cardiovascular Research Laboratory, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Chang
authors.affiliation: Graduate Institute of Pharmacology, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Jai
authors.initials: MJ
authors.lastname: Su
authors.affiliation: Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.|Vascular and Medicinal Research, Texas Heart Institute, Houston, Texas, USA.|Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Chu-Huang
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Laboratory, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.|Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Kuan-Cheng
authors.initials: KC
authors.lastname: Chang
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D008078:Cholesterol, LDL / Q000378:metabolism*; D004195:Disease Models, Animal; D004562:Electrocardiography; D055724:Electrophysiological Phenomena; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D009392:Nephrectomy; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000209:etiology; D020257:Ventricular Remodeling
chemical_list: D008078:Cholesterol, LDL; D051605:Kv Channel-Interacting Proteins