title: Cellular remodeling in heart failure disrupts K(ATP) channel-dependent stress tolerance.
abstract: ATP-sensitive potassium (K(ATP)) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K(ATP) channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor alpha induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K(ATP) channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K(ATP) channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by K(ATP) channel openers. Thus, disease-induced K(ATP) channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy.
authors.affiliation: Department of Medicine, Mayo Clinic, Mayo Foundation, Rochester, MN 55905, USA.
authors.forename: Denice M
authors.initials: DM
authors.lastname: Hodgson
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Zingman
authors.forename: Garvan C
authors.initials: GC
authors.lastname: Kane
authors.forename: Carmen
authors.initials: C
authors.lastname: Perez-Terzic
authors.forename: Martin
authors.initials: M
authors.lastname: Bienengraeber
authors.forename: Cevher
authors.initials: C
authors.lastname: Ozcan
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gumina
authors.forename: Darko
authors.initials: D
authors.lastname: Pucar
authors.forename: Fergus
authors.initials: F
authors.lastname: O'Coclain
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
authors.forename: Alexey E
authors.initials: AE
authors.lastname: Alekseev
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002303:Cardiac Output, Low / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D004140:Dinitrophenols / Q000494:pharmacology; D005260:Female; D015640:Ion Channel Gating; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D014475:Uncoupling Agents / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D002316:Cardiotonic Agents; D004140:Dinitrophenols; D015221:Potassium Channels; D016211:Transforming Growth Factor alpha; D014475:Uncoupling Agents; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D007545:Isoproterenol; D002118:Calcium