KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension

Garvan C. Kane, Atta Behfar, Roy B. Dyer, D. Fearghas O'Cochlain, Xiao Ke Liu, Denice M. Hodgson, Santiago Reyes, Takashi Miki, Susumu Seino, Andre Terzic

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86 Scopus citations


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 (KATP) channel, predisposed to heart failure and death. Defective decoding of hypertension-induced metabolic distress signals in the (KATP) channel knockout set in motion pathological calcium overload and aggravated cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway. Rescue of the failing (KATP) knockout phenotype was achieved by alternative control of myocardial calcium influx, bypassing uncoupled metabolic-electrical integration. The intact KCNJ11-encoded (KATP) 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.

Original languageEnglish (US)
Pages (from-to)2285-2297
Number of pages13
JournalHuman molecular genetics
Issue number15
StatePublished - Aug 1 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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