利拉鲁肽通过NRF2改善高糖诱导的内皮细胞损伤

doi:10.3969/j.issn.1006-5725.2024.15.002

Abstract

Abstract:

Objective This study aimed to investigate the effect and mechanism of Liraglutide on high glucose-induced vascular endothelial cell injury. Methods Human umbilical vein endothelial cells （HUVECs） were cultured and divided into 4 groups： control， high glucose stimulation （HG）， Liraglutide， and Liraglutide + HG group. ELISA was used to detect the secretion of inflammatory cytokines in each group， kits the levels of intracellular reactive oxygen species （ROS）， the activity of SOD2 and Gpx4，and the level of MDA， and Western blot and immun of luorescence method nuclear translocation of Nrf2. Results The HG groupexhibited a significantly higher levels of tumor necrosis factor （TNF?α）， interleukin （IL-1）， IL-6， as well as the levels of intracellular ROS and MDA， but less activity of SOD2 and Gpx4， less contents of NO， and less nuclear translocation of Nrf2， as compared with the control group. Compared with the HG group， the Liraglutide + HG grouppresented significantly higher levels of TNF?α， IL-1， and IL-6， but lower levels of intracellular ROS and MDA， less activities of SOD2 and Gpx4， less contents of NO and less nuclear translocation of Nrf2. Conclusion Liraglutide suppresses high glucose-induced endothelial cell injury by increasing the nuclear translocation of Nrf2.

Key words: endothelial cells, hyperglycemia, liraglutide, oxidative stress, NF-E2-related factor 2

CLC Number:

R453

Yunlong SUN,Zhe MENG,Xijia WANG,Lu. GAO. Liraglutide ameliorates high glucose⁃induced endothelial cell injuryvia Nrf2[J]. The Journal of Practical Medicine, 2024, 40(15): 2051-2055.

Figures/Tables 6

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References 26

1	CESTA C E， ROTEM R， BATEMAN B T， et al. Safety of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in Early Pregnancy ［J］. JAMA Intern Med， 2024， 184（2）： 144-152. doi:10.1001/jamainternmed.2023.6663 doi: 10.1001/jamainternmed.2023.6663
2	NEUEN B L， HEERSPINK H J L， VART P， et al. Estimated Lifetime Cardiovascular， Kidney， and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors， GLP-1 Receptor Agonists， and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria ［J］. Circulation， 2024， 149（6）： 450-462. doi:10.1161/circulationaha.123.067584 doi: 10.1161/circulationaha.123.067584
3	ZHU Y， XIA X， HE Q， et al. Diabetes-associated neutrophil NETosis： pathogenesis and interventional target of diabetic complications ［J］. Front Endocrinol （Lausanne）， 2023， 14： 1202463. doi:10.3389/fendo.2023.1202463 doi: 10.3389/fendo.2023.1202463
4	CYR A R， HUCKABY L V， SHIVA S S， et al. Nitric Oxide and Endothelial Dysfunction ［J］. Crit Care Clin， 2020， 36（2）： 307-321. doi:10.1016/j.ccc.2019.12.009 doi: 10.1016/j.ccc.2019.12.009
5	ALMUTAIRI M， BATRAN RUSSHER J R AL. Glucagon-like peptide-1 receptor action in the vasculature ［J］. Peptides， 2019， 111： 26-32. doi:10.1016/j.peptides.2018.09.002 doi: 10.1016/j.peptides.2018.09.002
6	ANDRIKOU E， TSIOUFIS C， ANDRIKOU I， et al. GLP-1 receptor agonists and cardiovascular outcome trials： An update ［J］. Hellenic J Cardiol， 2019， 60（6）： 347-351. doi:10.1016/j.hjc.2018.11.008 doi: 10.1016/j.hjc.2018.11.008
7	LE Y， WEI R， YANG K， et al. Liraglutide ameliorates palmitate-induced oxidative injury in islet microvascular endothelial cells through GLP-1 receptor/PKA and GTPCH1/eNOS signaling pathways ［J］. Peptides， 2020， 124： 170212. doi:10.1016/j.peptides.2019.170212 doi: 10.1016/j.peptides.2019.170212
8	LI J， ALBAJRAMI O， ZHUO M， et al. Decision Algorithm for Prescribing SGLT2 Inhibitors and GLP-1 Receptor Agonists for Diabetic Kidney Disease ［J］. Clin J Am Soc Nephrol， 2020， 15（11）： 1678-1688. doi:10.2215/cjn.02690320 doi: 10.2215/cjn.02690320
9	WITHAAR C， MEEMS L M G， MARKOUSIS-MAVROGENIS G， et al. The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction ［J］. Cardiovasc Res， 2021， 117（9）： 2108-2124. doi:10.1093/cvr/cvaa256 doi: 10.1093/cvr/cvaa256
10	GROUP G S R， NATHAN D M， LACHIN J M， et al. Glycemia Reduction in Type 2 Diabetes-Microvascular and Cardiovascular Outcomes ［J］. N Engl J Med， 2022， 387（12）： 1075-1088. doi:10.1056/nejmoa2200436 doi: 10.1056/nejmoa2200436
11	TRANG N N， CHUNG C C， LEE T W， et al. Empagliflozin and Liraglutide Differentially Modulate Cardiac Metabolism in Diabetic Cardiomyopathy in Rats ［J］. Int J Mol Sci， 2021， 22（3）： 1177. doi:10.3390/ijms22031177 doi: 10.3390/ijms22031177
12	LI R， SHAN Y， GAO L， et al. The Glp-1 Analog Liraglutide Protects Against Angiotensin Ⅱ and Pressure Overload-Induced Cardiac Hypertrophy via PI3K/Akt1 and AMPKa Signaling ［J］. Front Pharmacol， 2019， 10： 537. doi:10.3389/fphar.2019.00537 doi: 10.3389/fphar.2019.00537
13	WANG J， GUO R， MA X， et al. Liraglutide inhibits AngⅡ-induced cardiac fibroblast proliferation and ECM deposition through regulating miR-21/PTEN/PI3K pathway ［J］. Cell Tissue Bank， 2023， 24（1）： 125-137. doi:10.1007/s10561-022-10021-9 doi: 10.1007/s10561-022-10021-9
14	PRIMER K R， PSALTIS P J， TAN J T M， et al. The Role of High-Density Lipoproteins in Endothelial Cell Metabolism and Diabetes-Impaired Angiogenesis ［J］. Int J Mol Sci， 2020， 21（10）： 3633. doi:10.3390/ijms21103633 doi: 10.3390/ijms21103633
15	石建梅，王茜茜，韦晓洁. 铁蛋白自噬在糖尿病及其相关并发症发病机制中的研究进展［J］. 实用医学杂志， 2024， 40（3）： 417-422.
16	EL-ASHMAWY H M， SELIM F O， HOSNY T A M， et al. Association of low serum Meteorin like （Metrnl） concentrations with worsening of glucose tolerance， impaired endothelial function and atherosclerosis ［J］. Diabetes Res Clin Pract， 2019， 150： 57-63. doi:10.1016/j.diabres.2019.02.026 doi: 10.1016/j.diabres.2019.02.026
17	PONT C， ASCASO F J， GRZYBOWSKI A， et al. Corneal endothelial cell density during diabetes mellitus and ocular diabetes complications treatment ［J］. J Fr Ophtalmol， 2020， 43（8）： 794-798. doi:10.1016/j.jfo.2019.12.003 doi: 10.1016/j.jfo.2019.12.003
18	林丹红，全会标，欧倩滢，等. 利拉鲁肽对超重或肥胖男性2型糖尿病患者睾酮及性功能的影响［J］. 实用医学杂志， 2023， 39（7）： 894-898.
19	任丽君，高红红，宋瑞捧. 胰高血糖素样肽1受体基因遗传变异对利拉鲁肽治疗2型糖尿病患者疗效的影响［J］. 实用医学杂志， 2023， 39（2）： 164-169. doi:10.3969/j.issn.1006-5725.2023.02.007 doi: 10.3969/j.issn.1006-5725.2023.02.007
20	YAO Y， SONG Q， HU C， et al. Endothelial cell metabolic memory causes cardiovascular dysfunction in diabetes ［J］. Cardiovasc Res， 2022， 118（1）： 196-211. doi:10.1093/cvr/cvab013 doi: 10.1093/cvr/cvab013
21	BAHADORAN Z， MIRMIRAN P， GHASEMI A， et al. Type 2 Diabetes and Cancer： The Nitric Oxide Connection ［J］. Crit Rev Oncog， 2019， 24（3）： 235-242. doi:10.1615/critrevoncog.2019031256 doi: 10.1615/critrevoncog.2019031256
22	CHEN W H， CHEN C H， HSU M C， et al. Advances in the molecular mechanisms of statins in regulating endothelial nitric oxide bioavailability： Interlocking biology between eNOS activity and L-arginine metabolism ［J］. Biomed Pharmacother， 2024， 171： 116192. doi:10.1016/j.biopha.2024.116192 doi: 10.1016/j.biopha.2024.116192
23	ALCAZAR-LEYVA S， ZAPATA E， BERNAL-ALCANTARA D， et al. Thiamine pyrophosphate diminishes nitric oxide synthesis in endothelial cells ［J］. Int J Vitam Nutr Res， 2021， 91（5/6）： 491-499. doi:10.1024/0300-9831/a000650 doi: 10.1024/0300-9831/a000650
24	BONDI C D， HARTMAN HLTAN R J. NRF2 in kidney physiology and disease ［J］. Physiol Rep， 2024， 12（5）： e15961. doi:10.14814/phy2.15961 doi: 10.14814/phy2.15961
25	ZHANG Q， LIU J， DUAN H， et al. Activation of Nrf2/HO-1 signaling： An important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress ［J］. J Adv Res， 2021， 34： 43-63. doi:10.1016/j.jare.2021.06.023 doi: 10.1016/j.jare.2021.06.023
26	YAN X， SU Y， FAN X， et al. Liraglutide Improves the Angiogenic Capability of EPC and Promotes Ischemic Angiogenesis in Mice under Diabetic Conditions through an Nrf2-Dependent Mechanism ［J］. Cells， 2022， 11（23）： 3821. doi:10.3390/cells11233821 doi: 10.3390/cells11233821

组别	TNF-α	IL-1β	IL-6
对照组	5.08 ± 2.22	6.56 ± 2.41	5.45 ± 1.48
利拉鲁肽组	6.55 ± 2.15	4.75 ± 2.08	7.16 ± 3.36
HG组	370.85 ± 61.47^*	292.07 ± 43.05^*	312.13 ± 54.99^*
利拉鲁肽+HG组	204.18 ± 36.78^#	93.55 ± 17.09^#	70.83 ± 21.83^#
F值	145.10	203.10	145.40
P值	< 0.001	< 0.001	< 0.001

组别	ρ（ROS）（ng/L）	c（MDA）（nmol/L）	SOD2（U/mg）	Gpx4（μmol/g）
对照组	1.67 ± 0.81	0.84 ± 0.11	2.23 ± 0.14	179.91 ± 12.07
利拉鲁肽组	1.83 ± 0.75	0.83 ± 0.12	2.29 ± 0.18^*	190.96 ± 117.27
HG组	25.66 ± 3.72^*	3.08 ± 0.47^*	0.98 ± 0.13^*	85.90 ± 12.44^*
利拉鲁肽+HG组	10.83 ± 2.48^#	1.53 ± 0.16^#	1.77 ± 0.15^#	136.91 ± 22.06^#
F值	143.80	98.40	88.07	50.44
P值	< 0.001	< 0.001	< 0.001	< 0.001

组别	细胞活性（%）	NO水平（倍数）	NRF2核转位细胞比（%）
对照组	100.00 ± 0.68	1.00 ± 0.09	29.28 ± 4.99
利拉鲁肽组	103.82 ± 8.53	1.02 ± 0.07	30.41 ± 4.42
HG组	49.31 ± 7.47^*	0.48 ± 0.05^*	6.75 ± 1.15^*
利拉鲁肽+HG组	80.55 ± 8.63^#	0.78 ± 0.06^#	15.28 ± 1.59^#
F值	58.01	73.10	63.36
P值	< 0.001	< 0.001	< 0.001

组别	NRF2/GADPH （细胞胞浆水平）	NRF2/HistonH3 （细胞核水平）
对照组	0.98 ± 0.08	1.34 ± 0.09
利拉鲁肽组	1.03 ± 0.06	1.31 ± 0.09
HG组	0.14 ± 0.03^*	0.16 ± 0.05^*
利拉鲁肽+HG组	0.41 ± 0.05^#	0.97 ± 0.06^#
F值	202.40	191.70
P值	< 0.001	< 0.001

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Liraglutide ameliorates high glucose⁃induced endothelial cell injuryvia Nrf2

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