Published online before print August 24, 2006, doi: 10.1161/01.RES.0000243147.41792.93
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Submitted on January 25, 2006
Revised on July 24, 2006
Accepted on August 16, 2006
Molecular Mechanisms Mediating Inhibition of Human Large Conductance Ca2+-Activated K+ Channels by High Glucose
Tong Lu *;
From the Departments of Internal Medicine (T.L., H.-C.L.) and Anesthesiology (T.H., Z.S.K.), Mayo Clinic, Rochester, Minn.
* To whom correspondence should be addressed. 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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