Reactive oxygen species signaling facilitates FOXO-3a/FBXO-dependent vascular BK channel β 1 subunit degradation in diabetic mice

Tong Lu, Qiang Chai, Ling Yu, Livius V. D'Uscio, Zvonimir S. Katusic, Tongrong He, Hon Chi Lee

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Activity of the vascular large conductance Ca 2+-activated K + (BK) channel is tightly regulated by its accessory β 1 subunit (BK-β 1). Downregulation of BK-β 1 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-β 1 degradation and leads to diabetic BK channel dysfunction. Using cellular biology, patch clamp, and videomicroscopy techniques, we found that reduced BK-β 1 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-β 1 degradation in diabetic vessels. Suppression of the FOXO-3a/FBXO pathway prevented vascular BK-β 1 degradation and protected coronary function in diabetes.

Original languageEnglish (US)
Pages (from-to)1860-1868
Number of pages9
JournalDiabetes
Volume61
Issue number7
DOIs
StatePublished - Jul 2012

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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