| First Author | Lu T | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 10 | Pages | 2681-2690 |
| PubMed ID | 28465407 | Mgi Jnum | J:247997 |
| Mgi Id | MGI:5917654 | Doi | 10.2337/db17-0181 |
| Citation | Lu T, et al. (2017) Role of Nrf2 Signaling in the Regulation of Vascular BK Channel beta1 Subunit Expression and BK Channel Function in High-Fat Diet-Induced Diabetic Mice. Diabetes 66(10):2681-2690 |
| abstractText | The large conductance Ca2+-activated K+ (BK) channel beta1-subunit (BK-beta1) is a key modulator of BK channel electrophysiology and the downregulation of BK-beta1 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-beta1 and Nrf2 were markedly downregulated, whereas those of the nuclear factor-kappaB (NF-kappaB) and the muscle ring finger protein 1 (MuRF1 [a ubiquitin E3 ligase for BK-beta1]) were significantly upregulated in HFD mouse arteries. Adenoviral expression of Nrf2 suppressed the protein expressions of NF-kappaB and MuRF1 but enhanced BK-beta1 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-beta1-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-beta1 transcription, and attenuated MuRF1-dependent BK-beta1 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. |
