title: 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.
authors: b Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors: Tong
authors: T
authors: Lu
authors: a Department of Cardiology, The First Affiliated Hospital of Soochow University, 108 Shixin Street, Soochow, Jiangsu 215006, P.R. China.|b Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors: Bin
authors: B
authors: Jiang
authors: b Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors: Xiao-Li
authors: XL
authors: Wang
authors: b Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors: Hon-Chi
authors: HC
authors: Lee
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D057809:HEK293 Cells; D006801:Humans; D051664:Kv1.3 Potassium Channel; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D021381:Protein Transport / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; C494841:KCNMA1 protein, human; C494838:Kcnab1 protein, mouse; C465449:Kcnma1 protein, mouse; D051664:Kv1.3 Potassium Channel; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D044140:Receptor, Angiotensin, Type 1; D011994:Recombinant Proteins; D000804:Angiotensin II; C086491:NS 1619
keywords: BK channel; angiotensin II type 1 receptor; 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