Regulation of vascular large-conductance calcium-activated potassium channels by Nrf2 signalling

Yong Li, Xiao Li Wang, Xiaojing Sun, Qiang Chai, Jingchao Li, Benjamin Thompson, Win Kuang Shen, Tong Lu, Hon Chi Lee

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

BK channels are major ionic determinants of vasodilation. BK channel function is impaired in diabetic vessels due to accelerated proteolysis of its beta-1 (BK-β1) subunits in response to increased oxidative stress. The nuclear factor E2-related factor-2 (Nrf2) signalling pathway has emerged as a master regulator of cellular redox status, and we hypothesized that it plays a central role in regulating BK channel function in diabetic vessels. We found that Nrf2 expression was markedly reduced in db/db diabetic mouse aortas, and this was associated with significant downregulation of BK-β1. In addition, the muscle ring finger protein 1 (MuRF1), a known E-3 ligase targeting BK-β1 ubiquitination and proteasomal degradation, was significantly augmented. These findings were reproduced by knockdown of Nrf2 by siRNA in cultured human coronary artery smooth muscle cells. In contrast, adenoviral transfer of Nrf2 gene in these cells downregulated MuRF1 and upregulated BK-β1 expression. Activation of Nrf2 by dimethyl fumarate preserved BK-β1 expression and protected BK channel and vascular function in db/db coronary arteries. These results indicate that expression of BK-β1 is closely regulated by Nrf2 and vascular BK channel function can be restored by Nrf2 activation. Nrf2 should be considered a novel therapeutic target in the treatment of diabetic vasculopathy.

Original languageEnglish (US)
Pages (from-to)353-362
Number of pages10
JournalDiabetes and Vascular Disease Research
Volume14
Issue number4
DOIs
StatePublished - Jul 1 2017

Keywords

  • BK channel β1 subunit
  • Nrf2
  • coronary artery smooth muscle cell
  • dimethyl fumarate
  • muscle ring finger protein 1
  • type 2 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cardiology and Cardiovascular Medicine

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