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First published online on October 12, 2006.
 Copyright © 2006 by The Physiological Society
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Received August 18, 2006
Revised September 13, 2006
Accepted after revision October 9, 2006

Protection conferred by myocardial ATP-sensitive K+ channels in pressure overload-induced congestive heart failure revealed in KCNJ11 Kir6.2-null mutant

Satsuki Yamada1, Garvan C Kane1, Atta Behfar1, Xiao-Ke Liu1, Roy B Dyer1, Randolph S Faustino1, Takashi Miki2, Susumu Seino2, and Andre Terzic1*

1 Mayo Clinic
2 Kobe University

* To whom correspondence should be addressed. E-mail: terzic.andre{at}mayo.edu.

Ventricular load can precipitate development of the heart failure syndrome, yet the molecular components that control the cardiac adaptive response to imposed demand remain partly understood. Compromised ATP-sensitive K+ (KATP) channel function renders the heart vulnerable to stress, implicating this metabolic sensor in the homeostatic response that would normally prevent progression of cardiac disease. Here, pressure overload was imposed on the left ventricle by transverse aortic constriction in the wildtype and in mice lacking sarcolemmal KATP channels through Kir6.2 pore knockout (Kir6.2-KO). Despite equivalent haemodynamic loads, within 30 min of aortic constriction, Kir6.2-KO showed an aberrant prolongation of action potentials with intracellular calcium overload and ATP depletion, whereas wildtype maintained ionic and energetic handling. On catheterization, constricted Kir6.2-KO displayed compromised myocardial performance with elevated left ventricular end-diastolic pressure, not seen in the wildtype. Glyburide, a KATP channel inhibitor, reproduced the knockout phenotype in the wildtype, whereas the calcium channel antagonist, verapamil, prevented abnormal outcome in Kir6.2-KO. Within 48 h following aortic constriction, fulminant biventricular congestive heart failure, characterized by exercise intolerance, cardiac contractile dysfunction, hepatopulmonary congestion and ascites, halved the Kir6.2-KO cohort, while no signs of organ failure or mortality were seen in wildtype. Surviving Kir6.2-KO developed premature and exaggerated fibrotic myocardial hypertrophy associated with nuclear up-regulation of calcium-dependent pro-remodelling MEF2 and NF-AT pathways, precipitating chamber dilatation within 3 weeks. Thus, KATP channels appear mandatory in acute and chronic cardiac adaptation to imposed haemodynamic load, protecting against congestive heart failure and death.


Key words: ATP-sensitive potassium channel • Heart • Kir 6.2




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