Background: Diabetic (DM) inactivation of small conductance calcium-activated potassium (SK) channels contributes to coronary endothelial dysfunction. However, the mechanisms responsible for this down-regulation of endothelial SK channels are poorly understood. Thus, we hypothesized that the altered metabolic signaling in diabetes regulates endothelial SK channels and human coronary microvascular function.
Methods: Human atrial tissue, coronary arterioles and coronary artery endothelial cells (HCAECs) obtained from DM and non-diabetic (ND) patients (n = 12/group) undergoing cardiac surgery were used to analyze metabolic alterations, endothelial SK channel function, coronary microvascular reactivity and SK gene/protein expression/localization.
Results: The relaxation response of DM coronary arterioles to the selective SK channel activator SKA-31 and calcium ionophore A23187 was significantly decreased compared to that of ND arterioles (p < 0.05). Diabetes increases the level of NADH and the NADH/NAD+ ratio in human myocardium and HCAECs (p < 0.05). Increase in intracellular NADH (100 μM) in the HCAECs caused a significant decrease in endothelial SK channel currents (p < 0.05), whereas, intracellular application of NAD+ (500 μM) increased the endothelial SK channel currents (p < 0.05). Mitochondrial reactive oxygen species (mROS) of HCAECs and NADPH oxidase (NOX) and PKC protein expression in the human myocardium and coronary microvasculature were increased respectively (p < 0.05).
Conclusions: Diabetes is associated with metabolic changes in the human myocardium, coronary microvasculature and HCAECs. Endothelial SK channel function is regulated by the metabolite pyridine nucleotides, NADH and NAD+, suggesting that metabolic regulation of endothelial SK channels may contribute to coronary endothelial dysfunction in the DM patients with diabetes.
Keywords: Coronary microcirculation; Diabetes; Endothelial function; Endothelium-dependent hyperpolarization; Metabolic syndrome; SK channels.
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest.
Inactivation of Endothelial Small/Intermediate Conductance of Calcium-Activated Potassium Channels Contributes to Coronary Arteriolar Dysfunction in Diabetic Patients.J Am Heart Assoc. 2015 Aug 24;4(8):e002062. doi: 10.1161/JAHA.115.002062. J Am Heart Assoc. 2015. PMID: 26304940 Free PMC article.
Coronary endothelial dysfunction prevented by small-conductance calcium-activated potassium channel activator in mice and patients with diabetes.J Thorac Cardiovasc Surg. 2020 Feb 19:S0022-5223(20)30426-8. doi: 10.1016/j.jtcvs.2020.01.078. Online ahead of print. J Thorac Cardiovasc Surg. 2020. PMID: 32199659
Decreased coronary arteriolar response to KCa channel opener after cardioplegic arrest in diabetic patients.Version 2. Mol Cell Biochem. 2018 Aug;445(1-2):187-194. doi: 10.1007/s11010-017-3264-x. Epub 2018 Jan 5. Mol Cell Biochem. 2018. PMID: 29305679 Free PMC article.
Regulation of coronary blood flow during exercise.Physiol Rev. 2008 Jul;88(3):1009-86. doi: 10.1152/physrev.00045.2006. Physiol Rev. 2008. PMID: 18626066 Review.
Endothelial dysfunction and blood pressure alterations in K+-channel transgenic mice.Pflugers Arch. 2010 May;459(6):969-76. doi: 10.1007/s00424-010-0819-z. Epub 2010 Mar 28. Pflugers Arch. 2010. PMID: 20349244 Review.