Abstract 13518: Increased Protein and Increased Ca2+ Sensitivity are Both Responsible for the Increased Apamin-Sensitive K+ Current In Failing Human Ventricles
Introduction: Our recent studies showed that apamin-sensitive K+ current (IKAS), a major component of small conductance Ca2+-activated K+ (SK) current, is upregulated in human failing ventricles. The mechanisms of increased IKAS in heart failure (HF) remain unclear.
Hypothesis: Increased SK2 protein expression and calcium sensitivity can underlie the upregulation of IKAS in failing human ventricles.
Methods: HF Group included native hearts from 12 transplant recipients (age 45.1 ± 10.4 years; 11 males). Control Group (age 81.6 ± 9.6 years; 4 males) included core biopies from 8 patients with aortic stenosis and normal left ventricular ejection fraction (LVEF). Protein was extracted from LV. Western blot analysis was performed using anti-SK2 antibody and normalized with GAPDH. Steady-state Ca2+-sensitivity of IKAS was studied in isolated ventricular myocytes using patch-clamp techniques.
Results: The LVEF was 18.6 ± 4.2% for HF, and 63.4 ± 48.9% for control. Four (33%) HF patients had ischemic heart diseases. The IKAS activated with 1 µM intrapipette Ca2+ was significantly larger in the HF than in the control ventricular myocytes (IKAS at 0 mV with a holding potential of -70 mV: 4.92 ± 1.48 pA/pF, n = 22, vs. 1.48 ± 1.23 pA/pF, n = 8, p = 0.001). The Ca2+-dependence of IKAS was leftward shifted in HF compared to the control (HF: EC50, 371 ± 16 nM; Hill coefficient, 3.06 ± 0.28; Control: EC50, 518 ± 6 nM, Hill coefficient, 3.13 ± 0.05). SK2 protein was significantly overexpressed in HF compared to the control (normalized signal intensity: HF, 345 ± 77%, n = 6; control, 100 ± 13%, n = 5; p = 0.01).
Conclusions: Both SK2 channel overexpression and increased steady-state sensitivity to intracellular Ca2+ underlie the upregulation of IKAS in failing human ventricles.
- © 2011 by American Heart Association, Inc.