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

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.

KATP channel polymorphism is associated with left ventricular size in hypertensive individuals: a large-scale community-based study

“…Intact K ATP channels function as high-fidelity homeostatic rheostats that adjust membrane potential-dependent functions to match cellular energetic demand. Genetic or pharmacologic alterations predicted to abnormally increase or decrease the channel open probability have been reported to uncouple this metabolic signal decoding function, and thereby compromise cardiac stress responsiveness and increase susceptibility to heart disease (Bienengraeber et al 2004;Kane et al 2006;Yamada et al 2006;Lee et al 2007). Our findings with the K23 allele of the Kir6.2 pore, consistent with previous work with the ABCC9-encoded regulatory subunit (Olson et al 2007), uncover an interactive K ATP channel gene-environment substrate that confers cardiac disease risk in a predominantly Caucasian population.…”

Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress

“…Mice generated to lack the gene encoding Kir 6.2 (KCNJ11) are viable and lack K ATP channel activity in cardiomyocytes. Kir6.2 null animals were shown to have an impaired cardiac response to both acute and chronic stress [13][14][15][16]. Kir6.2 null mice were unable to maintain an elevated cardiac output following isoproterenol challenge and when subjected to treadmill stress tests exhibited a survival disadvantage [13].…”

“…Isoproterenol challenge in Kir6.2 null mice also induced repolarization arrhythmias leading to ventricular arrhythmias and sudden death [13]. Exposing Kir6.2 null mice to chronic stress, either by swimming or volume overload, revealed an impaired cardiac response similar to acute stress studies [14,15]. Following four weeks of chronic exercise, Kir6.2 mice exhibited reduced survival, cardiac hypertrophy and reduced cardiac output [14].…”

Defects in myoglobin oxygenation in KATP-deficient mouse hearts under normal and stress conditions characterized by near infrared spectroscopy and imaging

“…The K ATP channel is closed and therefore -silent‖ in cardiomyocytes under normal conditions [14] and [21] and Kir6.2 −/− mice have a normal life span and seem healthy under non-stress conditions. However when subjected to chronic stress or increased hemodynamic load, they develop dilated cardiomyopathy leading to heart failure and can die suddenly, probably due to aberrations in the components of energy metabolism manifested under stress conditions [14], [22], [23] and [24]. In response to acute metabolic insult, significant regional hypoxia was also revealed in Kir6.2 −/− hearts [14].…”