巨噬细胞的谷氨酰胺代谢重编程在心血管疾病中的作用

doi:10.3969/j.issn.1006-5725.2024.22.024

Abstract

Abstract:

Cardiovascular disease （CVD） poses a significant public health challenge in China， with both incidence and mortality rates increasing. The role of macrophage metabolic reprogramming in CVD has garnered growing attention due to its direct connection to the pathogenesis of the disease and potential therapeutic interventions. Glutamine （GLN）， a fundamental energy source for macrophages， plays a crucial role in this context. Alterations in GLN metabolism have substantial effects on macrophage phenotypic transformation， functional performance， and adaptive responses in the context of CVD. Therefore， this review aims to investigate the impact of GLN metabolic reprogramming on macrophages' contribution to the pathogenesis of CVD， specifically focusing on its involvement in atherosclerosis， myocardial infarction， and other cardiovascular conditions. Additionally， it will evaluate the potential of targeting GLN metabolic pathways as a therapeutic strategy.

Key words: glutamine metabolism, macrophages, cardiovascular disease, metabolic reprogramming

CLC Number:

R259

Xing CHEN,Yan DENG. The role of glutamine metabolic reprogramming in macrophages in cardiovascular disease[J]. The Journal of Practical Medicine, 2024, 40(22): 3262-3267.

Figures/Tables 1

References 65

1	刘明波，何新叶，杨晓红，等. 《中国心血管健康与疾病报告2023》要点解读［J］. 中国心血管杂志，2024，29（4）：305-324.
2	YANG Y， KARAMPOOR S， MIRZAEI R， et al. The interplay between microbial metabolites and macrophages in cardiovascular diseases： A comprehensive review ［J］. Int Immunopharmacol， 2023， 121. doi:10.1016/j.intimp.2023.110546 doi: 10.1016/j.intimp.2023.110546
3	JIN H R， WANG J， WANG Z J， et al. Lipid metabolic reprogramming in tumor microenvironment： From mechanisms to therapeutics ［J］. J Hematol Oncol， 2023， 16（1）： 103. doi:10.1186/s13045-023-01498-2 doi: 10.1186/s13045-023-01498-2
4	JEONG H， LEE B， HAN S J， et al. Glucose metabolic reprogramming in autoimmune diseases ［J］. Anim Cells Syst， 2023， 27（1）： 149-158. doi:10.1080/19768354.2023.2234986 doi: 10.1080/19768354.2023.2234986
5	DURANTE W. The Emerging Role of l-Glutamine in Cardiovascular Health and Disease ［J］. Nutrients， 2019， 11（9）：2092. doi:10.3390/nu11092092 doi: 10.3390/nu11092092
6	SHEN Y， ZHANG Y， LI W， et al. Glutamine metabolism： From proliferating cells to cardiomyocytes ［J］. Metabolism， 2021， 121： 154778. doi:10.1016/j.metabol.2021.154778 doi: 10.1016/j.metabol.2021.154778
7	MATéS J M， DI PAOLA F J， CAMPOS-SANDOVAL J A， et al. Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer ［J］. Semi Cell Develop Biol， 2020， 98： 34-43. doi:10.1016/j.semcdb.2019.05.012 doi: 10.1016/j.semcdb.2019.05.012
8	DURANTE W. Glutamine Deficiency Promotes Immune and Endothelial Cell Dysfunction in COVID-19 ［J］. Int J Mol Sci， 2023， 24（8）：7593. doi:10.3390/ijms24087593 doi: 10.3390/ijms24087593
9	SONG W， LI D， TAO L， et al. Solute carrier transporters： The metabolic gatekeepers of immune cells ［J］. Acta Pharm Sin B， 2020， 10（1）： 61-78. doi:10.1016/j.apsb.2019.12.006 doi: 10.1016/j.apsb.2019.12.006
10	SCALISE M， POCHINI L， PINGITORE P， et al. Cysteine is not a substrate but a specific modulator of human ASCT2 （SLC1A5） transporter ［J］. FEBS Lett， 2015， 589（23）： 3617-3623. doi:10.1016/j.febslet.2015.10.011 doi: 10.1016/j.febslet.2015.10.011
11	BHUTIA Y D， BABU E， RAMACHANDRAN S， et al. Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”： Novel Targets for the Design of a New Class of Anticancer Drugs ［J］. Cancer Res， 2015， 75（9）： 1782-1788. doi:10.1158/0008-5472.can-14-3745 doi: 10.1158/0008-5472.can-14-3745
12	YOO H C， PARK S J， NAM M， et al. A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells ［J］. Cell Metab， 2020， 31（2）： 267-83.e12. doi:10.1016/j.cmet.2019.11.020 doi: 10.1016/j.cmet.2019.11.020
13	YOO H C， YU Y C， SUNG Y， et al. Glutamine reliance in cell metabolism ［J］. Experi Mol Med， 2020， 52（9）： 1496-1516. doi:10.1038/s12276-020-00504-8 doi: 10.1038/s12276-020-00504-8
14	LI S， ZENG H， FAN J， et al. Glutamine metabolism in breast cancer and possible therapeutic targets ［J］. Biochem Pharmacol， 2023， 210： 115464. doi:10.1016/j.bcp.2023.115464 doi: 10.1016/j.bcp.2023.115464
15	CRUZAT V， MACEDO ROGERO M， NOEL KEANE K， et al. Glutamine： Metabolism and Immune Function， Supplementation and Clinical Translation ［J］. Nutrients， 2018， 10（11）：1564. doi:10.3390/nu10111564 doi: 10.3390/nu10111564
16	SHANG M， CAPPELLESSO F， AMORIM R， et al. Macrophage-derived glutamine boosts satellite cells and muscle regeneration ［J］. Nature， 2020， 587（7835）： 626-631. doi:10.1038/s41586-020-2857-9 doi: 10.1038/s41586-020-2857-9
17	PENG Y， ZHOU M， YANG H， et al. Regulatory Mechanism of M1/M2 Macrophage Polarization in the Development of Autoimmune Diseases ［J］. Mediators Inflamm， 2023， 2023： 8821610. doi:10.1155/2023/8821610 doi: 10.1155/2023/8821610
18	MENG D， YANG Q， WANG H， et al. Glutamine and asparagine activate mTORC1 independently of Rag GTPases ［J］. J Biol Chem， 2020， 295（10）： 2890-2899. doi:10.1074/jbc.ac119.011578 doi: 10.1074/jbc.ac119.011578
19	李泽桦，曾宇宏，冯丽芸，等. 氧化三甲胺促进M1型巨噬细胞极化加剧心肌梗死后心室重构［J］. 实用医学杂志，2022，38（20）：2531-2537，2544.
20	黄翔雨，申晓青， ZHOU Zheng，等. 细菌脂多糖及高迁移率族蛋白1对小鼠巨噬细胞M1/M2极化分型的影响［J］. 实用医学杂志，2018，34（6）：929-932.
21	FESTUCCIA W T. Regulation of Adipocyte and Macrophage Functions by mTORC1 and 2 in Metabolic Diseases ［J］. Mol Nutr Food Res， 2021， 65（1）： e1900768. doi:10.1002/mnfr.201900768 doi: 10.1002/mnfr.201900768
22	CORCORAN S E， O'NEILL L A. HIF1alpha and metabolic reprogramming in inflammation ［J］. J Clin Invest， 2016， 126（10）： 3699-3707. doi:10.1172/jci84431 doi: 10.1172/jci84431
23	KARUNAKARAN D， THRUSH A B， NGUYEN M A， et al. Macrophage Mitochondrial Energy Status Regulates Cholesterol Efflux and Is Enhanced by Anti-miR33 in Atherosclerosis ［J］. Circ Res， 2015， 117（3）： 266-278. doi:10.1161/circresaha.117.305624 doi: 10.1161/circresaha.117.305624
24	储莉，刘伏元，王烈成. 巨噬细胞极化及其在老年下肢动脉粥样硬化发生中的相关性［J］. 实用医学杂志，2015，31（6）：944-947.
25	XIAO Q， HOU R， XIE L， et al. Macrophage metabolic reprogramming and atherosclerotic plaque microenvironment： Fostering each other？［J］. Clin Transl Med， 2023，13（5）：e1257. doi:10.1002/ctm2.1257 doi: 10.1002/ctm2.1257
26	ROM O， GRAJEDA-IGLESIAS C， NAJJAR M， et al. Atherogenicity of amino acids in the lipid-laden macrophage model system in vitro and in atherosclerotic mice： A key role for triglyceride metabolism ［J］. J Nutr Biochem， 2017， 45： 24-38. doi:10.1016/j.jnutbio.2017.02.023 doi: 10.1016/j.jnutbio.2017.02.023
27	ZHANG H， WANG C， SUN H， et al. Glutamine supplementation alleviated aortic atherosclerosis in mice model and in vitro ［J］. Proteomics， 2024， 24（5）： e2300179. doi:10.1002/pmic.202300179 doi: 10.1002/pmic.202300179
28	PARK D， HAN C Z， ELLIOTT M R， et al. Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein ［J］. Nature， 2011， 477（7363）： 220-224. doi:10.1038/nature10340 doi: 10.1038/nature10340
29	MORIOKA S， PERRY J S A， RAYMOND M H， et al. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release ［J］. Nature， 2018， 563（7733）： 714-718. doi:10.1038/s41586-018-0735-5 doi: 10.1038/s41586-018-0735-5
30	TABAS I， BORNFELDT K E. Intracellular and Intercellular Aspects of Macrophage Immunometabolism in Atherosclerosis ［J］. Circ Res， 2020， 126（9）： 1209-1227. doi:10.1161/circresaha.119.315939 doi: 10.1161/circresaha.119.315939
31	FREEMERMAN A J， JOHNSON A R， SACKS G N， et al. Metabolic reprogramming of macrophages： Glucose transporter 1 （GLUT1）-mediated glucose metabolism drives a proinflammatory phenotype ［J］. J Biol Chem， 2014， 289（11）： 7884-9786. doi:10.1074/jbc.m113.522037 doi: 10.1074/jbc.m113.522037
32	FUKUZUMI M， SHINOMIYA H， SHIMIZU Y， et al. Endotoxin-induced enhancement of glucose influx into murine peritoneal macrophages via GLUT1 ［J］. Infect Imm， 2016， 64（1）： 108-112.
33	VATS D， MUKUNDAN L， ODEGAARD J I， et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation ［J］. Cell Metab， 2006， 4（1）： 13-24. doi:10.1016/j.cmet.2006.05.011 doi: 10.1016/j.cmet.2006.05.011
34	SUN X， LI Y， DENG Q， et al. Macrophage Polarization， Metabolic Reprogramming， and Inflammatory Effects in Ischemic Heart Disease ［J］. Front Immunol， 2022， 13： 934040. doi:10.3389/fimmu.2022.934040 doi: 10.3389/fimmu.2022.934040
35	YAKUPOVA E I， MALEEV G V， KRIVTSOV A V， et al. Macrophage polarization in hypoxia and ischemia/reperfusion： Insights into the role of energetic metabolism ［J］. Exp Biol Med （Maywood， NJ）， 2022， 247（11）： 958-971. doi:10.1177/15353702221080130 doi: 10.1177/15353702221080130
36	ZHANG Y. The essential role of glutamine metabolism in diabetic cardiomyopathy： A review ［J］. Medicine （Baltimore）， 2023， 102（47）： e36299. doi:10.1097/md.0000000000036299 doi: 10.1097/md.0000000000036299
37	NIZAMUTDINOVA I T， GULERIA R S， SINGH A B， et al. Retinoic acid protects cardiomyocytes from high glucose‐induced apoptosis through inhibition of NF‐κB signaling Pathway ［J］. J Cell Physiol， 2012， 228（2）： 380-392. doi:10.1002/jcp.24142 doi: 10.1002/jcp.24142
38	PAN Y， WANG Y， ZHAO Y， et al. Inhibition of JNK phosphorylation by a novel curcumin analog prevents high glucose-induced inflammation and apoptosis in cardiomyocytes and the development of diabetic cardiomyopathy ［J］. Diabetes， 2014， 63（10）： 3497-511. doi:10.2337/db13-1577 doi: 10.2337/db13-1577
39	MENG L， LIN H， HUANG X， et al. METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA ［J］. Cell Death Dis， 2022， 13（1）： 38. doi:10.1038/s41419-021-04484-z doi: 10.1038/s41419-021-04484-z
40	ZHAO R X， LI W J， LU Y R， et al. Increased peripheral proinflammatory T helper subsets contribute to cardiovascular complications in diabetic patients ［J］. Mediators Inflamm， 2014， 2014： 596967. doi:10.1155/2014/596967 doi: 10.1155/2014/596967
41	DU S， SHI H， XIONG L， et al. Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy ［J］. Frontiers Endocrinol， 2022， 13. doi:10.3389/fendo.2022.1011669 doi: 10.3389/fendo.2022.1011669
42	GAO M， MONIAN P， QUADRI N， et al. Glutaminolysis and Transferrin Regulate Ferroptosis ［J］. Molecular Cell， 2015， 59（2）： 298-308. doi:10.1016/j.molcel.2015.06.011 doi: 10.1016/j.molcel.2015.06.011
43	ZHANG M Q， WANG C C， PANG X B， et al. Role of macrophages in pulmonary arterial hypertension ［J］. Frontiers Immunol， 2023， 14. doi:10.3389/fimmu.2023.1152881 doi: 10.3389/fimmu.2023.1152881
44	AL-QAZAZI R， LIMA P D A， PRISCO S Z， et al. Macrophage-NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension［J］. Am J Respir Crit Care Med，2022，206（5）：608-624. doi:10.1164/rccm.202110-2274oc doi: 10.1164/rccm.202110-2274oc
45	LI M， RIDDLE S， KUMAR S， et al. Microenvironmental Regulation of Macrophage Transcriptomic and Metabolomic Profiles in Pulmonary Hypertension ［J］. Front Immunol， 2021， 12： 640718. doi:10.3389/fimmu.2021.640718 doi: 10.3389/fimmu.2021.640718
46	HE Y Y， YAN Y， JIANG X， et al. Spermine promotes pulmonary vascular remodelling and its synthase is a therapeutic target for pulmonary arterial hypertension ［J］. Eur Respir J， 2020，56（5）：2000522. doi:10.1183/13993003.00522-2020 doi: 10.1183/13993003.00522-2020
47	BERTERO T， OLDHAM W M， COTTRILL K A， et al. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension ［J］. J Clin Invest， 2016， 126（9）： 3313-3335. doi:10.1172/jci86387 doi: 10.1172/jci86387
48	GNATCHIK R A， BRITTAIN E L， SHAH A T， et al. Dysfunctional BMPR2 signaling drives an abnormal endothelial requirement for glutamine in pulmonary arterial hypertension ［J］. Pulm Circ， 2017， 7（1）： 186-199. doi:10.1086/690236 doi: 10.1086/690236
49	RYAN J J， ARCHER S L. The right ventricle in pulmonary arterial hypertension： disorders of metabolism， angiogenesis and adrenergic signaling in right ventricular failure ［J］. Circulation research， 2014， 115（1）： 176-188. doi:10.1161/circresaha.113.301129 doi: 10.1161/circresaha.113.301129
50	PIAO L， FANG Y H， PARIKH K， et al. Cardiac glutaminolysis： a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension ［J］. J Mol Med（Berlin， Germany）， 2013， 91（10）： 1185-1197. doi:10.1007/s00109-013-1064-7 doi: 10.1007/s00109-013-1064-7
51	PIRES R S， BRAGA P G S， SANTOS J M B， et al. l-Glutamine supplementation enhances glutathione peroxidase and paraoxonase-1 activities in HDL of exercising older individuals ［J］. Exp Gerontol， 2021， 156： 111584. doi:10.1016/j.exger.2021.111584 doi: 10.1016/j.exger.2021.111584
52	ZHANG X， QIN Y， WAN X， et al. Rosuvastatin exerts anti-atherosclerotic effects by improving macrophage-related foam cell formation and polarization conversion via mediating autophagic activities ［J］. J Transl Med， 2021， 19（1）： 62. doi:10.1186/s12967-021-02727-3 doi: 10.1186/s12967-021-02727-3
53	NICKLIN P， BERGMAN P， ZHANG B， et al. Bidirectional transport of amino acids regulates mTOR and autophagy ［J］. Cell， 2009， 136（3）： 521-534. doi:10.1016/j.cell.2008.11.044 doi: 10.1016/j.cell.2008.11.044
54	JOSEPH P， GLYNN R， LONN E， et al. Rosuvastatin for the prevention of venous thromboembolism： A pooled analysis of the HOPE-3 and JUPITER randomized controlled trials ［J］. Nat Cardiovasc Res， 2022， 118（3）： 897-903. doi:10.1093/cvr/cvab078 doi: 10.1093/cvr/cvab078
55	TIAN Z， ZHANG Y， LYU X. Promoting roles of KLF5 in myocardial infarction in mice involving microRNA-27a suppression and the following GFPT2/TGF-β/Smad2/3 axis activation ［J］. Cell Cycle （Georgetown， Tex）， 2021， 20（9）： 874-893. doi:10.1080/15384101.2021.1907512 doi: 10.1080/15384101.2021.1907512
56	KIM J， WANG C， DE SABANDO A R， et al. The Novel Small-Molecule SR18662 Efficiently Inhibits the Growth of Colorectal Cancer In Vitro and In Vivo ［J］. Mol Cancer Ther， 2019， 18（11）： 1973-1984. doi:10.1158/1535-7163.mct-18-1366 doi: 10.1158/1535-7163.mct-18-1366
57	TIAN Z， ZHANG Y， LYU X. Promoting roles of KLF5 in myocardial infarction in mice involving microRNA-27a suppression and the following GFPT2/TGF-beta/Smad2/3 axis activation ［J］. Cell Cycle， 2021， 20（9）： 874-893. doi:10.1080/15384101.2021.1907512 doi: 10.1080/15384101.2021.1907512
58	LI J， YE Y， LIU Z， et al. Macrophage mitochondrial fission improves cancer cell phagocytosis induced by therapeutic antibodies and is impaired by glutamine competition ［J］. Nat Cancer， 2022， 3（4）： 453-470. doi:10.1038/s43018-022-00354-5 doi: 10.1038/s43018-022-00354-5
59	CUI Z H， ZHANG X J， SHANG H Q， et al. Glutamine protects myocardial ischemia-reperfusion injury in rats through the PI3K/Akt signaling pathway ［J］. Eur Rev Med Pharmacolog Sci， 2020， 24（1）： 444-451. doi:10.23736/s0026-4725.19.05102-8 doi: 10.23736/s0026-4725.19.05102-8
60	SUFIT A， WEITZEL L B， HAMIEL C， et al. Pharmacologically dosed oral glutamine reduces myocardial injury in patients undergoing cardiac surgery： A randomized pilot feasibility trial ［J］. JPEN J Parenter Enteral Nutri， 2012， 36（5）： 556-561. doi:10.1177/0148607112448823 doi: 10.1177/0148607112448823
61	LIU F， LI Y， LIU G. MicroRNA-200c exacerbates the ischemia/reperfusion injury of heart through targeting the glutaminase （GLS）-mediated glutamine metabolism ［J］. Eur Rev Med Pharmacol Sci， 2017， 21（14）： 3282-3289.
62	HE B， XIAO J， REN A J， et al. Role of miR-1 and miR-133a in myocardial ischemic postconditioning ［J］. J Biomed Sci， 2011， 18（1）： 22. doi:10.1186/1423-0127-18-22 doi: 10.1186/1423-0127-18-22
63	JIN L， ALESI G N， KANG S. Glutaminolysis as a target for cancer therapy ［J］. Oncogene， 2016， 35（28）： 3619-3625. doi:10.1038/onc.2015.447 doi: 10.1038/onc.2015.447
64	DELGIR S， BASTAMI M， ILKHANI K， et al. The pathways related to glutamine metabolism， glutamine inhibitors and their implication for improving the efficiency of chemotherapy in triple-negative breast cancer ［J］. Mutat Res Rev Mutat Res， 2021， 787： 108366. doi:10.1016/j.mrrev.2021.108366 doi: 10.1016/j.mrrev.2021.108366
65	AHLUWALIA G S， GREM J L， HAO Z， et al. Metabolism and action of amino acid analog anti-cancer agents ［J］. Pharmacol Ther， 2009， 46（2）： 243-271.

[1]	Yong LIU,XiaoLei CHENG,Xiangli CUI,Hao TANG,Huanzhen CHEN. ROBO3 deficiency promotes chemotherapy⁃induced transition of macrophage to foam cell [J]. The Journal of Practical Medicine, 2024, 40(6): 787-795.
[2]	Chun LONG,Hongying BI,Changzhen YANG,Jiakai WANG,Yan TANG,Xu. LIU. Emodin upregulates the Sirt2 to attenuate LPS-induced oxidative stress response in RAW264.7 cells [J]. The Journal of Practical Medicine, 2024, 40(13): 1785-1790.
[3]	Sidong WEI,Kaige CHEN,Jixiang ZHANG,Juanjuan XUAN,Yaoquan WANG,Shun MIAO,Kaixin ZHAO,Weiwei WANG,Guoyong. CHEN. Changes and role of CD74 and CXCL9 positive macrophage subsets in rejection of rat liver transplantation [J]. The Journal of Practical Medicine, 2023, 39(23): 3027-3033.
[4]	Li′na MA,Zhenhua CAO,Bing. YANG. Correlation between sdLDL⁃C， CXCL12 and CVD in diabetic patients [J]. The Journal of Practical Medicine, 2023, 39(22): 2953-2957.
[5]	Xiaoxia WANG,Qiao HUANG,Min PENG,Tiemei. SHEN. Application of evidence⁃based standardized hospital discharge preparation service in elderly patients [J]. The Journal of Practical Medicine, 2023, 39(22): 3005-3009.
[6]	CHEN Le, QIU Yiling, JIANG Yanping. . Experience of implementing extracorporeal membrane oxygenation in the management of pregnant females complicated with critical cardiovascular diseases [J]. The Journal of Practical Medicine, 2022, 38(24): 3135-3140.
[7]	DAI Yan, BAO Mengying, ZENG Yanyu, LIU Yun, YE Yu. Using single ⁃ cell techniques to explore the characteristics of tumor ⁃ associated macrophages#br# [J]. The Journal of Practical Medicine, 2021, 37(3): 281-285.
[8]	ZHOU Junxiao, LI Junyan, LIU Kaijie, LIANG Yanxiao, WANG Hong. . The effect of lipopolysaccharide from Shewanella algae on the occurrence and development of colorectal adenoma [J]. The Journal of Practical Medicine, 2021, 37(21): 2717-2726.
[9]	LI Liu, YU Jianhua. . Research progress on risk factors and prevention and treatment of AIDS ⁃related cardiovascular diseases [J]. The Journal of Practical Medicine, 2021, 37(20): 2687-2691.
[10]	ZHU Peijun, LAI Chunhua, CHENG Mingwei, HE Yiheng, XU Shulan. . Promotive role of electrically biomembranes in bone regeneration through regulating the polarization of Macrophages [J]. The Journal of Practical Medicine, 2021, 37(10): 1257-1262.
[11]	NI Guo⁃ hua, LI Kun, YUAN Qiong. Pharmaceutical care for COVID ⁃ 19 patients with cardiovascular disease using antiviral drugs [J]. The Journal of Practical Medicine, 2020, 36(23): 3169-3173.

The role of glutamine metabolic reprogramming in macrophages in cardiovascular disease

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 1

References 65

Related Articles 11

Recommended Articles

Metrics

Comments