Effect of Ketone Body β-Hydroxybutyrate to Attenuate Inflammation-Induced Mitochondrial Oxidative Stress in Vascular Endothelial Cells

JI Li-wei; DENG Yan; LI Tao

doi:10.12182/20211160202

Volume 52 Issue 6

Nov. 2021

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JOURNAL OF SICHUAN UNIVERSITY (MEDICAL SCIENCES) > 2021 > 52(6): 954-959. > DOI: 10.12182/20211160202

JI Li-wei, DENG Yan, LI Tao. Effect of Ketone Body β-Hydroxybutyrate to Attenuate Inflammation-Induced Mitochondrial Oxidative Stress in Vascular Endothelial Cells[J]. Journal of Sichuan University (Medical Sciences), 2021, 52(6): 954-959. DOI: 10.12182/20211160202

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Effect of Ketone Body β-Hydroxybutyrate to Attenuate Inflammation-Induced Mitochondrial Oxidative Stress in Vascular Endothelial Cells

JI Li-wei^{1, 2},
DENG Yan²,
LI Tao^{1, 2, ,}

1.
Department of Anesthesiology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
2.
Laboratory of Mitochondria and Metabolism, Anesthesia and Operation Center, West China Hospital, Sichuan University, Chengdu 610041, China

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Corresponding author:
LI Tao, E-mail: scutaoli1981@scu.edu.cn
Received Date: April 08, 2021
Revised Date: November 11, 2021
Available Online: November 28, 2021
Published Date: November 19, 2021

Abstract

Abstract

Objective To investigate the regulatory function and mechanism of β-hydroxybutyrate (β-OHB), a ketone body, on the mitochondrial oxidative stress of inflammatory human umbilical vein endothelial cells (HUVECs).

Methods Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) were used to induce macrophages to release proinflammatory factors, and the culture supernatant was collected as a macrophage-conditioned medium (MCM) to culture HUVECs. A total of 7 groups of cells were used in the study: ①control group, or normal cultured HUVECs; ②MCM group, or the MCM-cultured HUVECs; groups ③ to ⑦ were all HUVECs co-cultured with different reagents, including ③MCM+β-OHB group, ④MCM+N-acetylcysteine (NAC) group, ⑤MCM+β-OHB+NAC group, ⑥MCM+β-OHB+histone deacetylase agonist ITSA1 group, and ⑦MCM+β-OHB+histone deacetylase inhibitor Entinostat group. MitoSOX immunofluorescence staining was conducted to analyzes the mitochondrial superoxide levels, real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was performed to examine the mRNA expression of antioxidant genes, and Seahorse mitochondrial energy analyzer was used to measure mitochondrial aerobic respiration capacity.

Results Compared with the control group, mitochondrial superoxide production was significantly increased in the MCM cultured HUVECs cells, while β-OHB treatment significantly inhibited mitochondrial superoxide production, which was accompanied by an increase in the mRNA expression of antioxidant genes, and significant increase in the basal mitochondrial oxygen consumption rate and respiratory reserve capacity. NAC treatment did not further enhance the protective effect of β-OHB on mitochondrial functions. In addition, ITSA1 treatment could completely offset the antioxidant and mitochondrial protective effects of β-OHB, and these stated effects were still maintained after Entinostat treatment.

Conclusion The ketone body β-OHB attenuates the mitochondrial oxidative stress of vascular endothelial cells through activating the antioxidant pathway and inhibiting histone deacetylase activity.
- Inflammation,
- Oxidative stress,
- Mitochondrial function,
- Human umbilical vein endothelial cells (HUVECs)

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[1]	SIES H. Oxidative stress: a concept in redox biology and medicine. Redox Biol,2015,4: 180–183. DOI: 10.1016/j.redox.2015.01.002
[2]	MURPHY M P, HOLMGREN A, LARSSON N G, et al. Unraveling the biological roles of reactive oxygen species. Cell Metab,2011,13(4): 361–366. DOI: 10.1016/j.cmet.2011.03.010
[3]	PIZZINO G, IRRERA N, CUCINOTTA M, et al. Oxidative stress: Harms and benefits for human health. Oxid Med Cell Longev,2017,2017: 8416763[2021-03-09]. https://doi.org/10.1155/2017/8416763.
[4]	SHADEL G S, HORVATH T L. Mitochondrial ROS signaling in organismal homeostasis. Cell,2015,163(3): 560–569. DOI: 10.1016/j.cell.2015.10.001
[5]	WILLEMS P H, ROSSIGNOL R, DIETEREN C E, et al. Redox homeostasis and mitochondrial dynamics. Cell Metab,2015,22(2): 207–218. DOI: 10.1016/j.cmet.2015.06.006
[6]	POPRAC P, JOMOVA K, SIMUNKOVA M, et al. Targeting free radicals in oxidative stress-related human diseases. Trends Pharmacol Sci,2017,38(7): 592–607. DOI: 10.1016/j.tips.2017.04.005
[7]	STEVEN S, FRENIS K, OELZE M, et al. Vascular inflammation and oxidative stress: Major triggers for cardiovascular disease. Oxid Med Cell Longev,2019,2019: 7092151[2021-03-09]. https://doi.org/10.1155/2019/7092151.
[8]	SHAO Y, SAREDY J, YANG W Y, et al. Vascular endothelial cells and innate immunity. Arterioscler Thromb Vasc Biol,2020,40(6): e138–e152[2021-03-11]. https://doi.org/10.1161/ATVBAHA.120.314330.
[9]	BRETON-ROMERO R, LAMAS S. Hydrogen peroxide signaling in vascular endothelial cells. Redox Biol,2014,2: 529–534[2021-03-09]. https://doi.org/10.1016/j.redox.2014.02.005.
[10]	YOUM Y H, NGUYEN K Y, GRANT R W, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med,2015,21(3): 263–269. DOI: 10.1038/nm.3804
[11]	DAYANG E Z, PLANTINGA J, TER ELLEN B, et al. Identification of LPS-activated endothelial subpopulations with distinct inflammatory phenotypes and regulatory signaling mechanisms. Front Immunol,2019,10: 1169021-03-09]. https://doi.org/10.3389/fimmu.2019.01169.
[12]	PUCHALSKA P, CRAWFORD P A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab,2017,25(2): 262–284. DOI: 10.1016/j.cmet.2016.12.022
[13]	CHENG C W, BITON M, HABER A L, et al. Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet. Cell,2019,178(5): 1115–1131.e1115. DOI: 10.1016/j.cell.2019.07.048
[14]	COX P J, KIRK T, ASHMORE T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab,2016,24(2): 256–268. DOI: 10.1016/j.cmet.2016.07.010
[15]	SHIMAZU T, HIRSCHEY M D, NEWMAN J, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science,2013,339(6116): 211–214. DOI: 10.1126/science.1227166
[16]	DENG Y, XIE M, LI Q, et al. Targeting mitochondria-inflammation circuit by beta-hydroxybutyrate mitigates HFpEF. Circ Res,2021,128(2): 232–245. DOI: 10.1161/CIRCRESAHA.120.317933
[17]	RAFII S, BUTLER J M, DING B S. Angiocrine functions of organ-specific endothelial cells. Nature,2016,529(7586): 316–325. DOI: 10.1038/nature17040
[18]	ANGELOVA P R, ABRAMOV A Y. Functional role of mitochondrial reactive oxygen species in physiology. Free Radic Biol Med,2016,100: 81–85. DOI: 10.1016/j.freeradbiomed.2016.06.005
[19]	SUGAMURA K, KEANEY J F, Jr. Reactive oxygen species in cardiovascular disease. Free Radic Biol Med,2011,51(5): 978–992. DOI: 10.1016/j.freeradbiomed.2011.05.004
[20]	SIES H, JONES D P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol,2020,21(7): 363–383. DOI: 10.1038/s41580-020-0230-3
[21]	BHATTACHARYA S.Reactive oxygen species and cellular defense system//Free radicals in human health and disease. New Delhi:Springer, 2015:17-29. .
[22]	MENZIES K J, ZHANG H, KATSYUBA E, et al. Protein acetylation in metabolism—Metabolites and cofactors. Nat Rev Endocrinol,2016,12(1): 43–60. DOI: 10.1038/nrendo.2015.181
[23]	KLOTZ L O, SANCHEZ-RAMOS C, PRIETO-ARROYO I, et al. Redox regulation of FoxO transcription factors. Redox Biol,2015,6: 51–72. DOI: 10.1016/j.redox.2015.06.019
[24]	PIETROCOLA F, GALLUZZI L, BRAVO-SAN PEDRO J M, et al. Acetyl coenzyme A: A central metabolite and second messenger. Cell Metab,2015,21(6): 805–821. DOI: 10.1016/j.cmet.2015.05.014

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Effect of Ketone Body β-Hydroxybutyrate to Attenuate Inflammation-Induced Mitochondrial Oxidative Stress in Vascular Endothelial Cells

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