Introduction and Objective: Impaired function of large-conductance Ca²+-activated K+ (BK) channels is associated with coronary artery dysfunction in diabetes mellitus. We previously reported that BK channel function is regulated by Src homology 3 (SH3) domain-containing protein 2 (Sorbs2) and its upstream regulator, nuclear factor erythroid 2-related factor 2 (Nrf2), in the coronary arterial smooth muscle cells (CASMCs) of type 2 diabetic animals. Whether this regulation pathway also presents in type 1 diabetic (T1D) vessels remains unknown.Methods: Using patch-clamp recordings, videomicroscopy, and molecular biology approaches, we investigated the mechanisms underlying coronary BK channelopathy and vasculopathy in non-obese diabetic (NOD) mice, a well-known autoimmune model of T1D.Results: Compared with non-diabetic controls, NOD mice, 7-9 weeks after diabetes onset, exhibited diminished whole-cell BK channel current densities in CASMCs from 431.20±62.13 pA/pF of controls to 203.98±41.47 pA/pF of NOD at +150 mV (n=14, p<0.05), leading to reduced coronary vasodilation induced by 100 μM NS-1619 (a BK channel activator) from 77.15±3.65% of controls to 40.41±2.60% of NOD (n=12, p<0.05). Inside-out single-channel recordings demonstrated a significant decrease in BK channel Ca2+ sensitivity in NOD mice. Furthermore, mRNA and protein levels of Nrf2, Sorbs2, and BK channels were markedly decreased in the arteries of NOD mice. A protein-RNA interaction assay confirmed that Sorbs2 proteins directly bind to the 5′- and 3′-untranslated regions of BK channel α-subunit mRNA.Conclusion: Our findings identify Sorbs2 as an RNA-binding protein that regulates BK channel expression and function in CASMCs. Downregulation of the Nrf2-Sorbs2 signaling pathway contributes to coronary BK channelopathy and vasculopathy in NOD mice.
X. Xiong: None. X. Sun: None. S. Asirvatham: None. H. Lee: None. T. Lu: None.
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