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(Circulation Research. 2006;99:607.)
© 2006 American Heart Association, Inc.

Cellular Biology

Molecular Mechanisms Mediating Inhibition of Human Large Conductance Ca²⁺-Activated K⁺ Channels by High Glucose

Tong Lu, Tongrong He, Zvonimir S. Katusic, Hon-Chi Lee

From the Departments of Internal Medicine (T.L., H.-C.L.) and Anesthesiology (T.H., Z.S.K.), Mayo Clinic, Rochester, Minn.

Correspondence to Tong Lu, MD, PhD, Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail lu.tong{at}mayo.edu

Diabetic vascular dysfunction is associated with an increase in reactive oxygen species (ROS). In this study, we hypothesized that hyperglycemia-induced ROS generation would impair the function of large conductance Ca²⁺-activated K⁺ (BK) channels, which are major determinants in vasorelaxation. We found that when cultured in high glucose (HG) (22 mmol/L), HEK293 cells showed a reduction in expressed hSlo current densities, as well as slowed activation and deactivation kinetics. When human coronary smooth muscle cells were cultured in HG, similar findings were observed for the BK currents. HG enhanced superoxide dismutase and suppressed catalase (CAT) expression in HEK293 cells, leading to a significant increase in intracellular ROS. The effects of HG were mimicked by hydrogen peroxide (H₂O₂), and hSlo functions were restored by CAT gene transfer. Peroxynitrite inhibited hSlo current density but did not change channel kinetics. The hSloC911A mutant was insensitive to the effects of HG and H₂O₂. Hence, imbalance of antioxidant enzymes plays a critical role in ROS generation in HG, impairing hSlo functions through H₂O₂-dependent oxidation at cysteine 911. This may represent an important fundamental mechanism that contributes to the impairment of vasodilation in diabetes.

Key Words: large conductance Ca²⁺-activated K⁺ channels • hyperglycemia • catalase • reactive oxygen species • gene transfer

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