title: Diet-induced obesity causes long QT and reduces transcription of voltage-gated potassium channels.
abstract: In humans, obesity is associated with long QT, increased frequency of premature ventricular complexes, and sudden cardiac death. The mechanisms of the pro-arrhythmic electrophysiologic remodeling of obesity are poorly understood. We tested the hypothesis that there is decreased expression of voltage-gated potassium channels in the obese heart, leading to long QT. Using implanted telemeters, we found that diet-induced obese (DIO) wild-type mice have impaired cardiac repolarization, demonstrated by long QT, as well as more frequent ventricular ectopy, similar to obese humans. DIO mice have reduced protein and mRNA levels of the potassium channel Kv1.5 caused by a reduction of the transcription factor cyclic AMP response element binding protein (CREB) in DIO hearts. We found that CREB knock-down by siRNA reduces Kv1.5, CREB binds to the Kv1.5 promoter in the heart, and CREB increases transcription of mouse and human Kv1.5 promoters. The reduction in CREB protein during lipotoxicity can be rescued by inhibiting protein kinase D (PKD). Our results identify a mechanism for obesity-induced electrophysiologic remodeling in the heart, namely PKD-induced reduction of CREB, which in turn decreases expression of the potassium channel Kv1.5.
authors.affiliation: Department of Medicine, Division of Cardiology, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Huang
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Amin
authors.forename: Michael
authors.initials: M
authors.lastname: Gurin
authors.forename: Elaine
authors.initials: E
authors.lastname: Wan
authors.forename: Edward
authors.initials: E
authors.lastname: Thorp
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.forename: John P
authors.initials: JP
authors.lastname: Morrow
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein; D059305:Diet, High-Fat / Q000009:adverse effects*; D015151:Immunoblotting; D051666:Kv1.5 Potassium Channel / Q000378:metabolism; D008133:Long QT Syndrome / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000209:etiology* / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051666:Kv1.5 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; C089212:protein kinase D; D011493:Protein Kinase C