Metabolic regulation of endothelial SK channels and human coronary microvascular function

INTERNATIONAL JOURNAL OF CARDIOLOGY

卷:312

Article

Liu, Yuhong²  Kabakov, Anatoli Y.¹  Xie, An³  Shi, Guangbin²  Singh, Arun K.²  Sodha, Neel R.²  Ehsan, Afshin²  Usheva, Anny²  Agbortoko, Vahid²  Koren, Gideon¹  Dudley, Samuel C., Jr.³  Sellke, Frank W.²  Feng, Jun² 

[1] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Cardiovasc Res Ctr, Providence, RI 02903 USA

[2] Brown Univ, Rhode Isl Hosp, Div Cardiothorac Surg, Alpert Med Sch, Providence, RI 02903 USA

[3] Univ Minnesota, Dept Med, Lillehei Heart Inst, Box 736 UMHC, Minneapolis, MN 55455 USA

关键词: Metabolic syndrome;    Diabetes;    SK channels;    Coronary microcirculation;    Endothelial function;    Endothelium-dependent hyperpolarization;   

DOI  :  10.1016/j.ijcard.2020.03.028

来源: Elsevier

【 摘 要 】

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 DMcoronary 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 mu M) in the HCAECs caused a significant decrease in endothelial SK channel currents (p < 0.05), whereas, intracellular application of NAD(+) (500 mu M) 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 thatmetabolic regulation of endothelial SK channelsmay contribute to coronary endothelial dysfunction in the DM patients with diabetes. (c) 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

【 授权许可】

Free