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

Research output: Contribution to journalArticle

86 Scopus citations

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 (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
Volume15
Issue number15
DOIs
StatePublished - Aug 1 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'KCNJ11 gene knockout of the Kir6.2 K<sub>ATP</sub> channel causes maladaptive remodeling and heart failure in hypertension'. Together they form a unique fingerprint.

  • Cite this