KATP channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response.
ABSTRACT ATP-sensitive K+ (K(ATP)) channels maintain cardiac homeostasis under stress, as revealed by murine gene knockout models of the KCNJ11-encoded Kir6.2 pore. However, the translational significance of K(ATP) channels in human cardiac physiology remains largely unknown. Here, the frequency of the minor K23 allele of the common functional Kir6.2 E23K polymorphism was found overrepresented in 115 subjects with congestive heart failure compared to 2,031 community-based controls (69 vs. 56%, P < 0.001). Moreover, the KK genotype, present in 18% of heart failure patients, was associated with abnormal cardiopulmonary exercise stress testing. In spite of similar baseline heart rates at rest among genotypic subgroups (EE: 72.2 ± 2.3, EK: 75.0 ± 1.8 and KK:77.1 ± 3.0 bpm), subjects with the KK genotype had a significantly reduced heart rate increase at matched workload (EE: 32.8 ± 2.7%, EK: 28.8 ± 2.1%, KK: 21.7 ± 2.6%, P < 0.05), at 75% of maximum oxygen consumption (EE: 53.9 ± 3.9%, EK: 49.9 ± 3.1%, KK: 36.8 ± 5.3%, P < 0.05), and at peak V(O2) (EE: 82.8 ± 6.0%, EK: 80.5 ± 4.7%, KK: 59.7 ± 8.1%, P < 0.05). Molecular modeling of the tetrameric Kir6.2 pore structure revealed the E23 residue within the functionally relevant intracellular slide helix region. Substitution of the wild-type E residue with an oppositely charged, bulkier K residue would potentially result in a significant structural rearrangement and disrupted interactions with neighboring Kir6.2 subunits, providing a basis for altered high-fidelity K(ATP) channel gating, particularly in the homozygous state. Blunted heart rate response during exercise is a risk factor for mortality in patients with heart failure, establishing the clinical relevance of Kir6.2 E23K as a biomarker for impaired stress performance and underscoring the essential role of K(ATP) channels in human cardiac physiology.
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ABSTRACT: ATP-sensitive K(+) channels (KATP ) are widely distributed and present in a number of tissues including muscle, pancreatic β cells and the brain. Their activity is regulated by adenine nucleotides characteristically being activated by falling ATP and rising ADP levels. Thus they link cellular metabolism with membrane excitability. Recent studies using genetically modified mice and genomic studies in patients have implicated KATP channels in a number of physiological and pathological processes. In this review, we focus on their role in cellular function and protection particularly in the cardiovascular system.British Journal of Pharmacology 09/2013; DOI:10.1111/bph.12407 · 5.07 Impact Factor
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ABSTRACT: Acetyl-CoA carboxylase 2 (ACC2) is an isoform of ACC functioning as a negative regulator of fatty acid β-oxidation. Spot14, a thyroid hormone responsive protein, and Mig12, a Spot14 paralog, have recently been identified as regulators of fatty acid synthesis targeting ACC1, a distinctive subtype of ACC. Here, we examined whether Spot14/Mig12 modulates ACC2. Nanoscale protein topography mapped putative protein-protein interactions between purified human Spot14/Mig12 and ACC2, validated by functional assays. Human ACC2 displayed consistent enzymatic activity, and homogeneous particle distribution was probed by atomic force microscopy. Citrate-induced polymerization and enzymatic activity of ACC2 were restrained by the addition of the recombinant Spot14/Mig12 heterocomplex but only partially by the oligo-heterocomplex, demonstrating that the heterocomplex is a designated metabolic inhibitor of human ACC2. Moreover, Spot14/Mig12 demonstrated a sequestering role preventing an initial ACC2 nucleation step during filamentous polymer formation. Thus, the Spot14/Mig12 heterocomplex controls human ACC2 polymerization and catalytic function, emerging as a previously unrecognized molecular regulator in catalytic lipid metabolism. © 2013 The Authors. Journal of Molecular Recognition published by John Wiley & Sons, Ltd.Journal of Molecular Recognition 12/2013; 26(12):679-88. DOI:10.1002/jmr.2313 · 3.01 Impact Factor
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ABSTRACT: ATP-sensitive potassium channels play an important role in myocardial electrical activity. Genetic disruption of these channels predisposes the myocardium to cardiac diseases. Herein we investigated whether two polymorphisms, E23K and I337V, located in the Kir6.2 subunit of ATP-sensitive potassium channels are associated with dilated cardiomyopathy (DCM) in a Chinese population. Blood was collected from DCM patients and controls. DNA was extracted for polymerase chain reaction, which was followed by DNA sequencing. The 2 polymorphisms were present in both DCM patients and normal controls. The frequencies of both the E23K and the I337V polymorphisms were not significantly different between DCM patients and normal controls. However, in DCM patients carrying the E23K polymorphism, the left ventricular end diastolic dimension (LVEDD) and the left atrial dimension (LAD) were significantly greater than those in DCM patients without the E23K polymorphism. Moreover, the occurrence of ventricular arrhythmias in DCM patients was also slightly increased in the presence of the E23K polymorphism (P < 0.05). We failed to identify an association between the I337V polymorphism and LVEDD, LAD, or ventricular arrhythmias in patients with DCM. The Kir6.2 E23K polymorphism in DCM patients of Han ethnicity may increase the risk of negative outcomes such as congestive heart failure and sudden cardiac death by affecting LVEDD and LAD.Genetics and molecular research: GMR 01/2013; 12(4):4383-92. DOI:10.4238/2013.October.10.4 · 0.85 Impact Factor