Downregulation of BK channel function and protein expression in coronary arteriolar smooth muscle cells of type 2 diabetic patients
| Autor: | Xiaojing Sun, Kevin L. Greason, Hon Chi Lee, Richard C. Daly, Qiang Chai, Jonathan D. Furuseth, Tong Lu, Guoqing Jiao, John M. Stulak, Yong Mei Cha, Xiao Li Wang |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty BK channel Physiology Large-Conductance Calcium-Activated Potassium Channel beta Subunits Myocytes Smooth Muscle Vasodilation Coronary Artery Disease 030204 cardiovascular system & hematology Muscle Smooth Vascular 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Arteriole Physiology (medical) Diabetes mellitus medicine.artery Internal medicine medicine Myocyte Humans Calcium Signaling Large-Conductance Calcium-Activated Potassium Channel alpha Subunits Microvessel Aged biology business.industry Original Articles Middle Aged medicine.disease Coronary Vessels Kinetics 030104 developmental biology Endocrinology Diabetes Mellitus Type 2 Case-Control Studies biology.protein Female Cardiology and Cardiovascular Medicine business Perfusion Ion Channel Gating Diabetic Angiopathies Signal Transduction |
| Zdroj: | Cardiovascular research. 115(1) |
| ISSN: | 1755-3245 |
| Popis: | Aims Type 2 diabetes (T2D) is strongly associated with cardiovascular morbidity and mortality in patients. Vascular large conductance Ca2+-activated potassium (BK) channels, composed of four pore-forming α subunits (BK-α), and four regulatory β1 subunits (BK-β1), are densely expressed in coronary arterial smooth muscle cells (SMCs) and play an important role in regulating vascular tone and myocardial perfusion. However, the role of BK channels in coronary microvascular dysfunction of human subjects with diabetes is unclear. In this study, we examined BK channel function and protein expression, and BK channel-mediated vasodilation in freshly isolated coronary arterioles from T2D patients. Methods and results Atrial tissues were obtained from 16 patients with T2D and 25 matched non-diabetic subjects during cardiopulmonary bypass procedure. Microvessel videomicroscopy and immunoblot analysis were performed in freshly dissected coronary arterioles and inside-out single BK channel currents was recorded in enzymatically isolated coronary arteriolar SMCs. We found that BK channel sensitivity to physiological Ca2+ concentration and voltage was downregulated in the coronary arteriolar SMCs of diabetic patients, compared with non-diabetic controls. BK channel kinetics analysis revealed that there was significant shortening of the mean open time and prolongation of the mean closed time in diabetic patients, resulting in a remarkable reduction of the channel open probability. Functional studies showed that BK channel activation by dehydrosoyasaponin-1 was diminished and that BK channel-mediated vasodilation in response to shear stress was impaired in diabetic coronary arterioles. Immunoblot experiments confirmed that the protein expressions of BK-α and BK-β1 subunits were significantly downregulated, but the ratio of BK-α/BK-β1 was unchanged in the coronary arterioles of T2D patients. Conclusions Our results demonstrated for the first time that BK channel function and BK channel-mediated vasodilation were abnormal in the coronary microvasculature of diabetic patients, due to decreased protein expression and altered intrinsic properties of BK channels. |
| Databáze: | OpenAIRE |
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