Abstract 3727: Inhibition of BK Channel Function and Exacerbation of Cardiac Ischemia/Reperfusion Injury by Diabetes and Angiotensin II Are Caveolae-Dependent
Background: We have recently found that Angiotensin II (AII) type 1 receptor (AT1R) and the large-conductance calcium-activated potassium channels (BK) are colocalized in coronary smooth muscle caveolae together with the AT1R signaling complex including Gq, c-Src and NOX-1. In this study, we examined the role of caveolae on AII-mediated effects on BK and on myocardial ischemia-reperfusion (I/R) injury, in control and streptozotocin-induced diabetic mice (DM).
Results: AII (2 μM) inhibited BK in coronary arterial smooth muscle cells (CASMC) from WT mice by 58% (89±21 vs 209±44 pA/pF baseline, n=9 *p<0.05) but had no effect in caveolin-1 knockout (Cav1−/−) mice (253±56 vs 207±60 pA/pF at baseline). BK was severely reduced in WT DM (22.1±7.3 pA/F) and AII had no effect (26.8±13.6 pA/pF, n=9). BK was preserved in Cav1−/− DM (155±28 pA/pF) without change by AII (133±31 pA/pF, n=9). Isolated hearts subjected to 40 min of global ischemia and 60 min of reperfusion produced an infarct size (IS) of 46.2±2.9% of area-at-risk (AAR) in WT (n=5) and this was exacerbated by pretreatment (50 min) with AII (2 μM, IS 81.7±4.3%*, n=7, *p<0.05), with IBTX (0.2 μM, a BK channel specific inhibitor, IS 68.2±9.3%*, n=7), or by diabetes (IS 90.4±4.6%*, n=7). In WT mice, the AII effects were abrogated by Losartan (10 μM, IS 49.0±4.5% AAR, n=8) or by NS1619 (10 μM, a BK channel activator, IS 49.7±7.5% AAR, n=5). However, in Cav1−/− mice, I/R injury was not exacerbated by AII with IS of 49.5±4.1% AAR (n=5), but by IBTX (IS 86.8±5.1%*, n=6).
Conclusions: Inhibition of BK by AII is caveolae-dependent. The deleterious effects of AII on myocardial I/R injury are dependent on the integrity of caveolae and modulated by BK channel activities. Activation of BK channels would abrogate the effects of AII and improve outcome. Hence, BK should be considered a therapeutic target in the treatment of acute coronary syndrome and in diabetes.