KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension.
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.
Kane
Garvan C
GC
Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Behfar
Atta
A
Dyer
Roy B
RB
O'Cochlain
D Fearghas
DF
Liu
Xiao-Ke
XK
Hodgson
Denice M
DM
Reyes
Santiago
S
Miki
Takashi
T
Seino
Susumu
S
Terzic
Andre
A
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
D019703:Calcineurin; D002118:Calcium; D002121:Calcium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel