Coronary arterial BK channel dysfunction exacerbates ischemia/reperfusion-induced myocardial injury in diabetic mice

Abstract

The large conductance Ca(2+)-activated K(+) (BK) channels, abundantly expressed in coronary artery smooth muscle cells (SMCs), play a pivotal role in regulating coronary circulation. A large body of evidence indicates that coronary arterial BK channel function is diminished in both type 1 and type 2 diabetes. However, the consequence of coronary BK channel dysfunction in diabetes is not clear. We hypothesized that impaired coronary BK channel function exacerbates myocardial ischemia/reperfusion (I/R) injury in streptozotocin-induced diabetic mice. Combining patch-clamp techniques and cellular biological approaches, we found that diabetes facilitated the colocalization of angiotensin II (Ang II) type 1 receptors and BK channel α-subunits (BK-α), but not BK channel β1-subunits (BK-β1), in the caveolae of coronary SMCs. This caveolar compartmentation in vascular SMCs not only enhanced Ang II-mediated inhibition of BK-α but also produced a physical disassociation between BK-α and BK-β1, leading to increased infarct size in diabetic hearts. Most importantly, genetic ablation of caveolae integrity or pharmacological activation of coronary BK channels protected the cardiac function of diabetic mice from experimental I/R injury in both in vivo and ex vivo preparations. Our results demonstrate a vascular ionic mechanism underlying the poor outcome of myocardial injury in diabetes. Hence, activation of coronary BK channels may serve as a therapeutic target for cardiovascular complications of diabetes.

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

“…Rabbit anti-Nrf2 (1:200; catalog #sc-722; Santa Cruz Biotechnology), rabbit anti–HO-1 (1:200; catalog #sc-10789; Santa Cruz Biotechnology), and mouse anti-MuRF1 (1:200; catalog #sc-398608; Santa Cruz Biotechnology), mouse GAPDH-horseradish peroxidase (HRP) (1:5,000; catalog #HRP-6004; Proteintech), and mouse anti–β-actin-HRP (1:10,000; catalog #A3854; Sigma-Aldrich, St. Louis, MO) antibodies were used in this study. Rabbit anti–BK-β1 antibody (1:200) was custom made as previously reported (4). NF-κB family member antibody sample kit (1:200; catalog #4766S) was purchased from Cell Signaling Technology Inc. (Danvers, MA).…”

“…The large-conductance calcium-activated potassium (BK) channels are abundantly expressed in coronary arterial smooth muscle cells (SMCs), playing an important role in regulating coronary circulation and myocardial perfusion (1–4). Functional vascular BK channels are composed of the pore-forming α-subunits and the regulatory β1-subunits (BK-β1) in 4:4 stoichiometry.…”

Diabetes Mellitus and Ischemic Heart Disease: The Role of Ion Channels

“…However, they demonstrated a normal expression and localization of these types of coronary microvasculature endothelial channels in diabetic patients, underlining that T2DM might cause a downregulation of these channels through post-translational modifications [ 79 ]. Moreover, in mice with T2DM, coronary BKCa potassium current dysfunction has been associated with higher and more extensive myocardial ischemia/reperfusion damage [ 80 ].…”

Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

“…Ang II-induced oxidative post-translational modification makes it possible to impair BK channel function in vascular smooth muscle (Ushio-Fukai and Alexander, 2006 ). In subsequent studies, Lu et al ( 2016 ) proposed a molecular scheme of a receptor-enzyme-channel-caveolae microdomain complex and found that the colocalization between AT1R and BK α-subunits in vascular SMCs produces a physical disassociation between BK α and BK β1-subunits, enhancing Ang II-mediated inhibition of BK channels in STZ-induced diabetic rats. Caveolae-Ang II signaling is involved in vascular BK channel regulation and facilitates BK channel and coronary dysfunction in diabetes, indicating that BK channels may present a potential new clinical target in the prevention and treatment of cardiovascular complications in diabetes.…”

“…To determine the physiological relevance of these findings, the effects of Ang II and NS-1619 on the vasoreactivity of coronary arterial rings were measured and the results suggested that the components of IBTX-sensitivity BK channels and Ang II-induced vasoconstriction was reduced in STZ-induced diabetic rats, which may suggest an increased vascular tone in diabetic vessels. A recent study from same group has shown that genetic knockout of Cav-1 gene attenuated the myocardial infarction-induced by ischemia-reperfusion injury in diabetic mice (Lu et al, 2016 ). Such diabetic effects on myocardial infarction could be mimicked by 2 μM Ang II or 0.1 μM IBTX on the Langendorff-perfused hearts of non-diabetic wild type mice.…”