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

Tong D Lu, Bin Jiang, Xiao Li Wang, Hon Chi Lee

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)992-1001
Number of pages10
JournalApplied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme
Volume41
Issue number9
DOIs
StatePublished - Sep 1 2016

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Keywords

  • angiotensin II type 1 receptor
  • BK channel
  • canal BK
  • cellule du muscle lisse des vaisseaux
  • diabetes
  • diabète
  • lésion myocardique par ischémie-reperfusion
  • myocardial ischemia/reperfusion injury
  • récepteur de type 1 de l’angiotensine II
  • vascular smooth muscle cell

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Nutrition and Dietetics
  • Physiology (medical)

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