Metabolic regulation of endothelial SK channels and human coronary microvascular function

Yuhong Liu, Anatoli Y. Kabakov, An Xie, Guangbin Shi, Arun K. Singh, Neel R. Sodha, Afshin Ehsan, Anny Usheva, Vahid Agbortoko, Gideon Koren, Samuel C. Dudley, Frank W. Sellke, Jun Feng

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalInternational Journal of Cardiology
StatePublished - Aug 1 2020

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© 2020 The Authors


  • Coronary microcirculation
  • Diabetes
  • Endothelial function
  • Endothelium-dependent hyperpolarization
  • Metabolic syndrome
  • SK channels


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