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

Abstract

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 + (K ATP ) 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 wild-type and in mice lacking sarcolemmal K ATP 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 wild-type 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 wild-type. Glyburide, a K ATP channel inhibitor, reproduced the knockout phenotype in the wild-type, 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 wild-type. 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, K ATP channels appear mandatory in acute and chronic cardiac adaptation to imposed haemodynamic load, protecting against congestive heart failure and death.

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.…”

“…Ventricular cardiomyocytes are rich in stress-responsive K ATP channels comprised pore-forming Kir6.2 and SUR2A regulatory subunits encoded by KCNJ11 and ABCC9, respectively (Zingman et al 2002;Yamada et al 2006). Their critical role in stress adaptation is exemplified by genetically defective channel complexes caused by ABCC9 mutations in human dilated cardiomyopathy (Bienengraeber et al 2004) and Kcnj11 −/− mice, vulnerable to hypertensioninduced heart failure .…”

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

“…For functional analysis both circumferential shortening velocity that is a preload independent parameter of ventricular function, and fractional shortening that is dependent on loading and heart rate were determined. Myocardial velocity of left ventricular circumferential shortening (Vcf expressed in circumferences per second) was calculated as Vcf = [(LVDd-LVDs)/LVDd]/(ejection time) as described [21].…”

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].…”