title: KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension.
abstract: Heart failure is a growing epidemic, with systemic hypertension a major risk factor for development of disease. However, the molecular determinants that prevent the transition from a state of hypertensive load to that of overt cardiac failure remain largely unknown. Here in experimental hypertension, knockout of the KCNJ11 gene, encoding the Kir6.2 pore-forming subunit of the sarcolemmal ATP-sensitive potassium (K(ATP)) channel, predisposed to heart failure and death. Defective decoding of hypertension-induced metabolic distress signals in the K(ATP) channel knockout set in motion pathological calcium overload and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway. Rescue of the failing K(ATP) knockout phenotype was achieved by alternative control of myocardial calcium influx, bypassing uncoupled metabolic-electrical integration. The intact KCNJ11-encoded K(ATP) channel is thus a required safety element preventing hypertension-induced heart failure, with channel dysfunction a molecular substrate for stress-associated channelopathy in cardiovascular disease.
authors.affiliation: Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Garvan C
authors.initials: GC
authors.lastname: Kane
authors.forename: Atta
authors.initials: A
authors.lastname: Behfar
authors.forename: Roy B
authors.initials: RB
authors.lastname: Dyer
authors.forename: D Fearghas
authors.initials: DF
authors.lastname: O'Cochlain
authors.forename: Xiao-Ke
authors.initials: XK
authors.lastname: Liu
authors.forename: Denice M
authors.initials: DM
authors.lastname: Hodgson
authors.forename: Santiago
authors.initials: S
authors.lastname: Reyes
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D006973:Hypertension / Q000150:complications* / Q000235:genetics; D008659:Metabolic Diseases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D020257:Ventricular Remodeling / Q000235:genetics*; D000099161:Kcnj11 Channel
chemical_list: D019703:Calcineurin; D002118:Calcium; D002121:Calcium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel