Reactive oxygen species signaling facilitates FOXO-3a/FBXO-dependent vascular BK channel β1 subunit degradation in diabetic mice.
Reactive oxygen species signaling facilitates FOXO-3a/FBXO-dependent vascular BK channel β1 subunit degradation in diabetic mice.
复制标题
作者：
Lu T;Chai Q;Yu L;d'Uscio LV;Katusic ZS;He T;Lee HC
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.
登录
查看更多内容
影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1161/hypertensionaha.110.150623
发表时间：
2010-04
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
d'Uscio LV;Smith LA;Katusic ZS
通讯作者：
Katusic ZS
影响因子：
20.1
作者：
McGahon MK;Dash DP;Arora A;Wall N;Dawicki J;Simpson DA;Scholfield CN;McGeown JG;Curtis TM
通讯作者：
Curtis TM
影响因子：
5.3
作者：
Brunet, A;Park, J;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1085/jgp.116.3.411
发表时间：
2000-09
期刊：
The Journal of general physiology
影响因子：
--
作者：
Cox DH;Aldrich RW
通讯作者：
Aldrich RW