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

doi:10.1016/j.ijcard.2020.03.028

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

Medicine - Cardiology Division

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	1-9
Number of pages	9
Journal	International Journal of Cardiology
Volume	312
DOIs	https://doi.org/10.1016/j.ijcard.2020.03.028
State	Published - Aug 1 2020

Bibliographical note

Funding Information:
This research project was supported by the NIH 1R01HL127072-01A1 , 1R01 HL136347-01 , NIGMS / NIH grant (pilot project) 1P20GM103652 and AHA -Grant-in-Aid- 15GRNT25710105 to J.F.; R01-HL-46716 and U54GM115677 to F.W.S, and RO1HL128831, to F.W.S & A.U.

Funding Information:
This research project was mainly supported by the National Institutes of Health (NIH) 1R01HL127072-01A1 , 1R01 HL136347-01 , National Institute of General Medical Science (NIGMS) of the NIH [ 5P20-GM103652 (Pilot Project and CORE)] and AHA -Grant-in-Aid (# 15GRNT25710105 ) to J.F. This work was supported in part by R01-HL46716 to F.W.S., RO1HL128831 to F.W.S and A.U.

Publisher Copyright:
© 2020 The Authors

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ijcard.2020.03.028

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@article{34ab1f1ee4be46e6887f72c2eb041236,

title = "Metabolic regulation of endothelial SK channels and human coronary microvascular function",

abstract = "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",

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

note = "Funding Information: This research project was supported by the NIH 1R01HL127072-01A1 , 1R01 HL136347-01 , NIGMS / NIH grant (pilot project) 1P20GM103652 and AHA -Grant-in-Aid- 15GRNT25710105 to J.F.; R01-HL-46716 and U54GM115677 to F.W.S, and RO1HL128831, to F.W.S & A.U. Funding Information: This research project was mainly supported by the National Institutes of Health (NIH) 1R01HL127072-01A1 , 1R01 HL136347-01 , National Institute of General Medical Science (NIGMS) of the NIH [ 5P20-GM103652 (Pilot Project and CORE)] and AHA -Grant-in-Aid (# 15GRNT25710105 ) to J.F. This work was supported in part by R01-HL46716 to F.W.S., RO1HL128831 to F.W.S and A.U. Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

month = aug,

day = "1",

doi = "10.1016/j.ijcard.2020.03.028",

language = "English (US)",

volume = "312",

pages = "1--9",

journal = "International Journal of Cardiology",

issn = "0167-5273",

publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Metabolic regulation of endothelial SK channels and human coronary microvascular function

AU - Liu, Yuhong

AU - Kabakov, Anatoli Y.

AU - Xie, An

AU - Shi, Guangbin

AU - Singh, Arun K.

AU - Sodha, Neel R.

AU - Ehsan, Afshin

AU - Usheva, Anny

AU - Agbortoko, Vahid

AU - Koren, Gideon

AU - Dudley, Samuel C.

AU - Sellke, Frank W.

AU - Feng, Jun

N1 - Funding Information: This research project was supported by the NIH 1R01HL127072-01A1 , 1R01 HL136347-01 , NIGMS / NIH grant (pilot project) 1P20GM103652 and AHA -Grant-in-Aid- 15GRNT25710105 to J.F.; R01-HL-46716 and U54GM115677 to F.W.S, and RO1HL128831, to F.W.S & A.U. Funding Information: This research project was mainly supported by the National Institutes of Health (NIH) 1R01HL127072-01A1 , 1R01 HL136347-01 , National Institute of General Medical Science (NIGMS) of the NIH [ 5P20-GM103652 (Pilot Project and CORE)] and AHA -Grant-in-Aid (# 15GRNT25710105 ) to J.F. This work was supported in part by R01-HL46716 to F.W.S., RO1HL128831 to F.W.S and A.U. Publisher Copyright: © 2020 The Authors

PY - 2020/8/1

Y1 - 2020/8/1

N2 - 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.

AB - 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.

KW - Coronary microcirculation

KW - Diabetes

KW - Endothelial function

KW - Endothelium-dependent hyperpolarization

KW - Metabolic syndrome

KW - SK channels

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UR - http://www.scopus.com/inward/citedby.url?scp=85081971862&partnerID=8YFLogxK

U2 - 10.1016/j.ijcard.2020.03.028

DO - 10.1016/j.ijcard.2020.03.028

M3 - Article

C2 - 32199682

AN - SCOPUS:85081971862

SN - 0167-5273

VL - 312

SP - 1

EP - 9

JO - International Journal of Cardiology

JF - International Journal of Cardiology

ER -

Metabolic regulation of endothelial SK channels and human coronary microvascular function

Abstract

Bibliographical note

Keywords

UN SDGs

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