Key result
Pharmacological activation of coronary BK channels with NS1619 significantly reduced ischemia/reperfusion-induced myocardial infarct size in diabetic mice from 90.7% to 27.7%.
Why the study?
Does activation of coronary BK channels or ablation of caveolae integrity reduce myocardial ischemia/reperfusion injury in diabetic mice?
Does activation of coronary BK channels or ablation of caveolae integrity reduce myocardial ischemia/reperfusion injury in diabetic mice?
Absolute Event Rate: 27.7% vs 90.7%
p-value: p=3.1x10^-6
Activation of coronary BK channels or genetic ablation of caveolae integrity protects diabetic mouse hearts from ischemia/reperfusion injury, suggesting a potential therapeutic target for diabetic cardiovascular complications.
May protect diabetic hearts from I/R injury via BK activation; hypothesis-generating and requires clinical validation.
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.
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Lü et al. (2016) studied Myocardial ischemia-reperfusion injury in diabetes. NS1619 (BK channel activator) vs. Vehicle/Control was evaluated on Myocardial infarct size (% of total heart weight) (p=3.1x10^-6). Pharmacological activation of coronary BK channels with NS1619 significantly reduced ischemia/reperfusion-induced myocardial infarct size in diabetic mice from 90.7% to 27.7%.
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