The large conductance Ca2+-activated K+ (BK) channel ß1 subunit (BK-ß1) is a key modulator of BK channel electrophysiology and the downregulation of BK-ß1 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-ß1 and Nrf2 were markedly downregulated, while those of the nuclear factor ¿B (NF-¿B) and the muscle ring finger protein 1 (MuRF1, an ubiquitin E3 ligase for BK-ß1) were significantly upregulated in HFD mouse arteries. Adenoviral expression of Nrf2 suppressed the protein expressions of NF-¿B and MuRF1 but enhanced BK-ß1 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-ß1-mediated channel activation was diminished in HFD mice. Importantly, activation of Nrf2 by dimethyl fumarate significantly reduced the body weight and blood glucose levels of HFD mice, enhanced BK-ß1 transcription and attenuated MuRF1-dependent BK-ß1 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.

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