Role of Nrf2 signaling in the regulation of vascular BK channel β1 subunit expression and BK channel function in high-fat diet–induced diabetic mice

Tong D Lu, Xiaojing Sun, Yong Li, Qiang Chai, Xiao Li Wang, Hon Chi Lee

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

The large conductance Ca2+-activated K+ (BK) channel β1-subunit (BK-b1) is a key modulator of BK channel electrophysiology and the downregulation of BK-b1 protein expression in vascular smooth muscle cells (SMCs) underlies diabetic vascular dysfunction. In this study, we hypothesized that the nuclear factor erythroid-2–related factor 2 (Nrf2) signaling pathway plays a significant role in the regulation of coronary BK channel function and vasodilation in high-fat diet (HFD)–induced obese/diabetic mice. We found that the protein expressions of BK-b1 and Nrf2 were markedly downregulated, whereas those of the nuclear factor-kB (NF-kB) and the muscle ring finger protein 1 (MuRF1 [a ubiquitin E3 ligase for BK-b1]) were significantly upregulated in HFD mouse arteries. Adenoviral expression of Nrf2 suppressed the protein expressions of NF-kB and MuRF1 but enhanced BK-b1 mRNA and protein expressions in cultured coronary SMCs. Knockdown of Nrf2 resulted in reciprocal changes of these proteins. Patch-clamp studies showed that coronary BK-b1–mediated channel activation was diminished in HFD mice. Importantly, the activation of Nrf2 by dimethyl fumarate significantly reduced the body weight and blood glucose levels of HFD mice, enhanced BK-b1 transcription, and attenuated MuRF1-dependent BK-b1 protein degradation, which in turn restored coronary BK channel function and BK channel–mediated coronary vasodilation in HFD mice. Hence, Nrf2 is a novel regulator of BK channel function with therapeutic implications in diabetic vasculopathy.

Original languageEnglish (US)
Pages (from-to)2681-2690
Number of pages10
JournalDiabetes
Volume66
Issue number10
DOIs
StatePublished - Oct 1 2017

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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