Referenced in: none

Automatically associated channels: Kir1.1 , Kir6.2

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

Authors: 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

Journal, date & volume: Hum. Mol. Genet., 2006 Aug 1 , 15, 2285-97

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16782803

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.