Reactive Oxygen Species Signaling Facilitates FOXO-3a/FBXO-dependent Vascular BK Channel β1 Subunit Degradation in Diabetic Mice
- Tong Lu1⇓,
- Qiang Chai1,2,
- Ling Yu1,3,
- Livius V. d’Uscio4,
- Zvonimir S. Katusic4,
- Tongrong He4 and
- Hon-Chi Lee1
- 1Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
- 2Department of Physiology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, People’s Republic of China
- 3Department of Cardiology, Fujian Province Hospital, Fuzhou, People’s Republic of China
- 4Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota
- Corresponding author: Tong Lu, .
Activity of the vascular large conductance Ca2+-activated K+ (BK) channel is tightly regulated by its accessory β1 subunit (BK-β1). Downregulation of BK-β1 expression in diabetic vessels is associated with upregulation of the forkhead box O subfamily transcription factor-3a (FOXO-3a)–dependent F-box–only protein (FBXO) expression. However, the upstream signaling regulating this process is unclear. Overproduction of reactive oxygen species (ROS) is a common finding in diabetic vasculopathy. We hypothesized that ROS signaling cascade facilitates the FOXO-3a/FBXO-mediated BK-β1 degradation and leads to diabetic BK channel dysfunction. Using cellular biology, patch clamp, and videomicroscopy techniques, we found that reduced BK-β1 expression in streptozotocin (STZ)-induced diabetic mouse arteries and in human coronary smooth muscle cells (SMCs) cultured with high glucose was attributable to an increase in protein kinase C (PKC)-β and NADPH oxidase expressions and accompanied by attenuation of Akt phosphorylation and augmentation of atrogin-1 expression. Treatment with ruboxistaurin (a PKCβ inhibitor) or with GW501516 (a peroxisome proliferator–activated receptor δ activator) reduced atrogin-1 expression and restored BK channel-mediated coronary vasodilation in diabetic mice. Our results suggested that oxidative stress inhibited Akt signaling and facilitated the FOXO-3a/FBXO-dependent BK-β1 degradation in diabetic vessels. Suppression of the FOXO-3a/FBXO pathway prevented vascular BK-β1 degradation and protected coronary function in diabetes.
- Received November 28, 2011.
- Accepted March 3, 2012.
- © 2012 by the American Diabetes Association.
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