Potential role of SIRT1 in unexplained recurrent spontaneous abortion

doi:10.3969/j.issn.1674-8115.2022.10.013

Abstract

Abstract:

Unexplained recurrent spontaneous abortion (URSA) is also known as alloimmune recurrent abortion. It is suggested that the main pathogenesis of URSA is immune imbalance at the maternal-fetal interface, abnormal trophoblast invasion and abnormal placental angiogenesis. Existing studies have revealed the important role of SIRT1 gene in the field of reproduction and the regulation of immune diseases. However, there is still a lack of systematic and comprehensive research overview on the mechanism of SIRT1 in improving URSA. SIRT1 may affect oxidative stress and autophagy by regulating the acetylation process of histones and key transcription factors, thus participating in numerous feedback loops and networks of URSA occurrence and development. Finally, SIRT1 can play a role in regulating trophoblast cell invasion and maternal-fetal interface angiogenesis. At the same time, the production of proinflammatory cytokines is suppressed to improve the excessive maternal immune inflammatory response during pregnancy. The activity of SIRT1 determines its deacetylation ability, which is crucial for downstream pathways and protein stability. Therefore, improving its activity is of great significance for improving URSA. Studies have shown that metformin and resveratrol can activate SIRT1 and protect SIRT1 and its downstream target proteins, which may be potential therapeutic agents for URSA. Based on the function of SIRT1, this article reviews the potential role of SIRT1 in the pathogenesis of URSA and the exogenous drugs targeting SIRT1 activation, in order to provide reference for the prevention and treatment of URSA in clinical research.

Key words: unexplained recurrent spontaneous abortion (URSA), sirtuin 1 (SIRT1), trophoblast cell, angiogenesis, immune

CLC Number:

R714.21

LIU Ziwei, CAO Wenwen, WANG Yunrui, FENG Xiaoling. Potential role of SIRT1 in unexplained recurrent spontaneous abortion[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(10): 1466-1473.

TrendMD

References 77

1	自然流产诊治中国专家共识(2020年版) [J]. 中国实用妇科与产科杂志, 2020, 36(11): 1082-1090.
	Consensus of Chinese Experts on the Diagnosis and Treatment of Spontaneous Abortion (2020 Edition) [J]. Chin J Pract Gynecol Obstet, 2020, 36(11): 1082-1090.
2	POPESCU F, JASLOW C R, KUTTEH W H. Recurrent pregnancy loss evaluation combined with 24-chromosome microarray of miscarriage tissue provides a probable or definite cause of pregnancy loss in over 90% of patients[J]. Hum Reprod, 2018, 33(4): 579-587.
3	HOU Y, LI J P, LIU Q, et al. The optimal timing of immunotherapy may improve pregnancy outcome in women with unexplained recurrent pregnancy loss: a perspective follow-up study in northeastern China[J]. Am J Reprod Immunol, 2020, 83(4): e13225.
4	YU L, ZHANG Y, XIONG J F, et al. Activated γδ T cells with higher CD107a expression and inflammatory potential during early pregnancy in patients with recurrent spontaneous abortion[J]. Front Immunol, 2021, 12: 724662.
5	LIU Y F, GAO S J, ZHAO Y J, et al. Decidual natural killer cells: a good nanny at the maternal-fetal interface during early pregnancy[J]. Front Immunol, 2021, 12: 663660.
6	KARBASFOROOSHAN H, ROOHBAKHSH A, KARIMI G. SIRT1 and microRNAs: the role in breast, lung and prostate cancers[J]. Exp Cell Res, 2018, 367(1): 1-6.
7	QIU Y Q, ZHOU X Y, LIU Y, et al. The role of sirtuin-1 in immune response and systemic lupus erythematosus[J]. Front Immunol, 2021, 12: 632383.
8	SHEN P, DENG X, CHEN Z, et al. SIRT1: a potential therapeutic target in autoimmune diseases[J]. Front Immunol, 2021, 12: 779177.
9	LIU Y, ZHANG M Q, ZHANG H J, et al. Anthocyanins inhibit airway inflammation by downregulating the NF-κB pathway via the miR-138-5p/SIRT1 axis in asthmatic mice[J]. Int Arch Allergy Immunol, 2022, 183(5): 539-551.
10	ARUL NAMBI RAJAN K, KHATER M, SONCIN F, et al. Sirtuin1 is required for proper trophoblast differentiation and placental development in mice[J]. Placenta, 2018, 62: 1-8.
11	ZHAO H, WONG R J, STEVENSON D K. The impact of hypoxia in early pregnancy on placental cells[J]. Int J Mol Sci, 2021, 22(18): 9675.
12	KNÖFLER M, HAIDER S, SALEH L, et al. Human placenta and trophoblast development: key molecular mechanisms and model systems[J]. Cell Mol Life Sci, 2019, 76(18): 3479-3496.
13	POLLHEIMER J, VONDRA S, BALTAYEVA J, et al. Regulation of placental extravillous trophoblasts by the maternal uterine environment[J]. Front Immunol, 2018, 9: 2597.
14	SUN X H, TONG X M, HAO Y Q, et al. Abnormal Cullin1 neddylation-mediated p21 accumulation participates in the pathogenesis of recurrent spontaneous abortion by regulating trophoblast cell proliferation and differentiation[J]. Mol Hum Reprod, 2020, 26(5): 327-339.
15	ZHANG S N, DING J L, WANG J Y, et al. CXCL5 downregulation in villous tissue is correlated with recurrent spontaneous abortion[J]. Front Immunol, 2021, 12: 717483.
16	XIONG L L, YE X, CHEN Z, et al. Advanced maternal age-associated SIRT1 deficiency compromises trophoblast epithelial-mesenchymal transition through an increase in vimentin acetylation[J]. Aging Cell, 2021, 20(10): e13491.
17	LEE K M, SEO H W, KWON M S, et al. SIRT1 negatively regulates invasive and angiogenic activities of the extravillous trophoblast[J]. Am J Reprod Immunol, 2019, 82(4): e13167.
18	CHAKRABORTY D, RUMI M A K, SOARES M J. NK cells, hypoxia and trophoblast cell differentiation[J]. Cell Cycle, 2012, 11(13): 2427-2430.
19	JOO H Y, YUN M Y, JEONG J, et al. SIRT1 deacetylates and stabilizes hypoxia-inducible factor-1α (HIF-1α) via direct interactions during hypoxia[J]. Biochem Biophys Res Commun, 2015, 462(4): 294-300.
20	CHEN X, LU Y, ZHANG Z G, et al. Intercellular interplay between Sirt1 signalling and cell metabolism in immune cell biology[J]. Immunology, 2015, 145(4): 455-467.
21	DING J L, ZHANG Y, CAI X P, et al. Crosstalk between trophoblast and macrophage at the maternal-fetal interface: current status and future perspectives[J]. Front Immunol, 2021, 12: 758281.
22	TANNAHILL G M, CURTIS A M, ADAMIK J, et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α[J]. Nature, 2013, 496(7444): 238-242.
23	PRUTSCH N, FOCK V, HASLINGER P, et al. The role of interleukin-1β in human trophoblast motility[J]. Placenta, 2012, 33(9): 696-703.
24	GONZALEZ M, NEUFELD J, REIMANN K, et al. Expansion of human trophoblastic spheroids is promoted by decidualized endometrial stromal cells and enhanced by heparin-binding epidermal growth factor-like growth factor and interleukin-1 Β[J]. Mol Hum Reprod, 2011, 17(7): 421-433.
25	WANG X H, XU S, ZHOU X Y, et al. Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk[J]. Nat Commun, 2021, 12(1): 3428.
26	SINGH M, ACHARYA N, SHUKLA S, et al. Comparative study of endometrial & subendometrial angiogenesis in unexplained infertile versus normal fertile women[J]. Indian J Med Res, 2021, 154(1): 99-107.
27	LI D, ZHENG L W, ZHAO D H, et al. The role of immune cells in recurrent spontaneous abortion[J]. Reprod Sci, 2021, 28(12): 3303-3315.
28	ALMASRY S M, ELMANSY R A, ELFAYOMY A K, et al. Ultrastructure alteration of decidual natural killer cells in women with unexplained recurrent miscarriage: a possible association with impaired decidual vascular remodelling[J]. J Mol Histol, 2015, 46(1): 67-78.
29	POTENTE M, GHAENI L, BALDESSARI D, et al. SIRT1 controls endothelial angiogenic functions during vascular growth[J]. Genes Dev, 2007, 21(20): 2644-2658.
30	HUANG Y J, NAN G X. Oxidative stress-induced angiogenesis[J]. J Clin Neurosci, 2019, 63: 13-16.
31	KRZYWINSKA E, KANTARI-MIMOUN C, KERDILES Y, et al. Loss of HIF-1α in natural killer cells inhibits tumour growth by stimulating non-productive angiogenesis[J]. Nat Commun, 2017, 8(1): 1597.
32	WANG W N, SUN W X, CHENG Y L, et al. Role of sirtuin-1 in diabetic nephropathy[J]. J Mol Med (Berl), 2019, 97(3): 291-309.
33	CHEN X Y, JIANG L M, WANG C C, et al. Hypoxia inducible factor and microvessels in peri-implantation endometrium of women with recurrent miscarriage[J]. Fertil Steril, 2016, 105(6): 1496-1502.e4.
34	CHEN X, MAN G, LIU Y, et al. Physiological and pathological angiogenesis in endometrium at the time of embryo implantation[J]. Am J Reprod Immunol, 2017, 78(2). doi: 10.1111/aji.12693.
35	TICCONI C, PIETROPOLLI A, DI SIMONE N, et al. Endometrial immune dysfunction in recurrent pregnancy loss[J]. Int J Mol Sci, 2019, 20(21): 5332.
36	EHSANI M, MOHAMMADNIA-AFROUZI M, MIRZAKHANI M, et al. Female unexplained infertility: a disease with imbalanced adaptive immunity[J]. J Hum Reprod Sci, 2019, 12(4): 274-282.
37	PIRES DA SILVA J, MONCEAUX K, GUILBERT A, et al. SIRT1 protects the heart from ER stress-induced injury by promoting eEF2K/eEF2-dependent autophagy[J]. Cells, 2020, 9(2): 426.
38	GERMIC N, FRANGEZ Z, YOUSEFI S, et al. Regulation of the innate immune system by autophagy: monocytes, macrophages, dendritic cells and antigen presentation[J]. Cell Death Differ, 2019, 26(4): 715-727.
39	DERETIC V. Autophagy in inflammation, infection, and immunometabolism[J]. Immunity, 2021, 54(3): 437-453.
40	MATSUZAWA-ISHIMOTO Y, HWANG S, CADWELL K. Autophagy and inflammation[J]. Annu Rev Immunol, 2018, 36: 73-101.
41	QIN X Y, SHEN H H, ZHOU W J, et al. Insight of autophagy in spontaneous miscarriage[J]. Int J Biol Sci, 2022, 18(3): 1150-1170.
42	TAN H X, YANG S L, LI M Q, et al. Autophagy suppression of trophoblast cells induces pregnancy loss by activating decidual NK cytotoxicity and inhibiting trophoblast invasion[J]. Cell Commun Signal, 2020, 18(1): 73.
43	NG F, TANG B L. Sirtuins' modulation of autophagy[J]. J Cell Physiol, 2013, 228(12): 2262-2270.
44	GANESAN R, HOS N J, GUTIERREZ S, et al. Salmonella typhimurium disrupts Sirt1/AMPK checkpoint control of mTOR to impair autophagy[J]. PLoS Pathog, 2017, 13(2): e1006227.
45	XIANG H, LIU S, ZONG C, et al. A single nucleotide polymorphism in the MTOR gene is associated with recurrent spontaneous abortion in the Chinese female population[J]. Syst Biol Reprod Med, 2015, 61(4): 205-210.
46	ZHU X X, CHU H Y, JIANG S, et al. Sirt1 ameliorates systemic sclerosis by targeting the mTOR pathway[J]. J Dermatol Sci, 2017, 87(2): 149-158.
47	WANG J L, SONG X Q, TAN G J, et al. NAD⁺ improved experimental autoimmune encephalomyelitis by regulating SIRT1 to inhibit PI3K/Akt/mTOR signaling pathway[J]. Aging, 2021, 13(24): 25931-25943.
48	CHUNG C, SEO W, SILWAL P, et al. Crosstalks between inflammasome and autophagy in cancer[J]. J Hematol Oncol, 2020, 13(1): 100.
49	PARK S, SHIN J, BAE J, et al. SIRT1 alleviates LPS-induced IL-1β production by suppressing NLRP3 inflammasome activation and ROS production in trophoblasts[J]. Cells, 2020, 9(3): 728.
50	BAHIA W, SOLTANI I, ABIDI A, et al. Identification of genes and miRNA associated with idiopathic recurrent pregnancy loss: an exploratory data mining study[J]. BMC Med Genomics, 2020, 13(1): 75.
51	TAKEDA-WATANABE A, KITADA M, KANASAKI K, et al. SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells[J]. Biochem Biophys Res Commun, 2012, 427(1): 191-196.
52	HODGE G, TRAN H B, REYNOLDS P N, et al. Lymphocyte senescence in COPD is associated with decreased sirtuin 1 expression in steroid resistant pro-inflammatory lymphocytes[J]. Ther Adv Respir Dis, 2020, 14: 1753466620905280.
53	ESCANDE C, CHINI C C S, NIN V, et al. Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice[J]. J Clin Invest, 2010, 120(2): 545-558.
54	Guideline Group on Rpl ESHRE, ATIK R B, CHRISTIANSEN O B, et al. ESHRE guideline: recurrent pregnancy loss[J]. Hum Reprod Open, 2018, 2018(2): hoy004.
55	ST-GERMAIN L E, CASTELLANA B, BALTAYEVA J, et al. Maternal obesity and the uterine immune cell landscape: the shaping role of inflammation[J]. Int J Mol Sci, 2020, 21(11): 3776.
56	GONZÁLEZ F, CONSIDINE R V, ABDELHADI O A, et al. Saturated fat ingestion promotes lipopolysaccharide-mediated inflammation and insulin resistance in polycystic ovary syndrome[J]. J Clin Endocrinol Metab, 2019, 104(3): 934-946.
57	PFLUGER P T, HERRANZ D, VELASCO-MIGUEL S, et al. Sirt1 protects against high-fat diet-induced metabolic damage[J]. Proc Natl Acad Sci USA, 2008, 105(28): 9793-9798.
58	THAN N G, HAHN S, ROSSI S W, et al. Editorial: fetal-maternal immune interactions in pregnancy[J]. Front Immunol, 2019, 10: 2729.
59	LIU G W, BI Y J, XUE L X, et al. Dendritic cell SIRT1-HIF1α axis programs the differentiation of CD4⁺ T cells through IL-12 and TGF-β1[J]. Proc Natl Acad Sci USA, 2015, 112(9): E957-E965.
60	ROBERTSON S A, CARE A S, MOLDENHAUER L M. Regulatory T cells in embryo implantation and the immune response to pregnancy[J]. J Clin Invest, 2018, 128(10): 4224-4235.
61	LUO J, WANG Y Q, QI Q R, et al. Sinomenine improves embryo survival by regulating Th1/Th2 balance in a mouse model of recurrent spontaneous abortion[J]. Med Sci Monit, 2021, 27: e927709.
62	WANG W J, SUNG N, GILMAN-SACHS A, et al. T helper (Th) cell profiles in pregnancy and recurrent pregnancy losses: Th1/Th2/Th9/Th17/Th22/tfh cells[J]. Front Immunol, 2020, 11: 2025.
63	LIMAGNE E, THIBAUDIN M, EUVRARD R, et al. Sirtuin-1 activation controls tumor growth by impeding Th17 differentiation via STAT3 deacetylation[J]. Cell Rep, 2017, 19(4): 746-759.
64	MARQUES H S, DE BRITO B B, DA SILVA F A F, et al. Relationship between Th17 immune response and cancer[J]. World J Clin Oncol, 2021, 12(10): 845-867.
65	NOVAKOVIC R, RAJKOVIC J, GOSTIMIROVIC M, et al. Resveratrol and reproductive health[J]. Life (Basel), 2022, 12(2): 294.
66	HUANG X Z, SUN J, CHEN G, et al. Resveratrol promotes diabetic wound healing via SIRT1-FOXO1-c-myc signaling pathway-mediated angiogenesis[J]. Front Pharmacol, 2019, 10: 421.
67	HANNAN N J, BROWNFOOT F C, CANNON P, et al. Resveratrol inhibits release of soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin and improves vascular dysfunction-implications as a preeclampsia treatment[J]. Sci Rep, 2017, 7(1): 1819.
68	OCHIAI A, KURODA K, OZAKI R, et al. Resveratrol inhibits decidualization by accelerating downregulation of the CRABP2-RAR pathway in differentiating human endometrial stromal cells[J]. Cell Death Dis, 2019, 10(4): 276.
69	KURODA K, OCHIAI A, BROSENS J J. The actions of resveratrol in decidualizing endometrium: acceleration or inhibition? [J]. Biol Reprod, 2020, 103(6): 1152-1156.
70	OCHIAI A, KURODA K, IKEMOTO Y, et al. Influence of resveratrol supplementation on IVF-embryo transfer cycle outcomes[J]. Reprod Biomed Online, 2019, 39(2): 205-210.
71	TULIPANO G. Integrated or independent actions of metformin in target tissues underlying its current use and new possible applications in the endocrine and metabolic disorder area[J]. Int J Mol Sci, 2021, 22(23): 13068.
72	GUO W R, LIU J, CHENG L D, et al. Metformin alleviates steatohepatitis in diet-induced obese mice in a SIRT1-dependent way[J]. Front Pharmacol, 2021, 12: 704112.
73	SONG Y M, LEE Y H, KIM J W, et al. Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway[J]. Autophagy, 2015, 11(1): 46-59.
74	HUNG C H, CHAN S H, CHU P M, et al. Metformin regulates oxLDL-facilitated endothelial dysfunction by modulation of SIRT1 through repressing LOX-1-modulated oxidative signaling[J]. Oncotarget, 2016, 7(10): 10773-10787.
75	ZHANG Y, LIU W F, ZHONG Y Q, et al. Metformin corrects glucose metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis via inhibiting the TLR4/NF-κB/PFKFB3 signaling in trophoblasts: implication for a potential therapy of preeclampsia[J]. Oxid Med Cell Longev, 2021, 2021: 1806344.
76	XU X X, ZHANG S S, LIN H L, et al. Metformin promotes regeneration of the injured endometrium via inhibition of endoplasmic reticulum stress-induced apoptosis[J]. Reprod Sci, 2019, 26(4): 560-568.
77	MOON J, LEE S Y, CHOI J W, et al. Metformin ameliorates Scleroderma via inhibiting Th17 cells and reducing mTOR-STAT3 signaling in skin fibroblasts[J]. J Transl Med, 2021, 19(1): 192.

[1]	NI Shuyi, JIANG Zhao, WANG Zhongtao, HE Shumei. Effect of salidroside on the immune function of BCG-infected macrophages [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(4): 426-433.
[2]	HUANG Zhouxuan, SHAO Jingbo. Research progress in the treatment of chronic primary immune thrombocytopenia [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(4): 508-516.
[3]	CHEN Yongyu, HUANG Yiren, CHEN Zheyi, ZHOU Bingqian, CHEN Shiyu, ZHENG Yingxia. Expression of serpin family E member 1 in gastric cancer and its mechanisms in promoting gastric cancer [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(2): 150-160.
[4]	LI Guanghui, FENG Xiaoling. Research progress on ferroptosis of placental cells in recurrent spontaneous abortion [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(10): 1383-1389.
[5]	HU Fei, CAI Xiaohan, CHENG Rui, JI Shiyu, MIAO Jiaxin, ZHU Yan, FAN Guangjian. Progress in translational research on immunotherapy for osteosarcoma [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(7): 814-821.
[6]	ZHANG Yong, LI Weihong, CHENG Zhipeng, WANG bin, WANG Siheng, WANG Yubin. Research status of receptor-interacting protein kinase 1 in regulating cancer progression and immune response [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(6): 788-794.
[7]	ZHENG Mengyi, MAO Jialiang, ZOU Zhiguo, ZHANG Ruilei, ZHANG Hou, LI Shiguang. Predictive value of systemic immune inflammation index and somatic symptom scale-China in the occurrence of in-hospital major adverse cardiovascular events after first-episode of acute myocardial infarction undergoing PCI [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(3): 334-341.
[8]	YANG Jingyu, CHEN Liubao, WANG Kangtai, YANG Xingzhi, YU Haitao. Establishment and evaluation of nomogram for differential diagnosis of systemic lupus erythematosus based on laboratory indications [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(2): 204-211.
[9]	LIU Jiayu, HUANG Fang, HAO Siguo. A case of chronic myelomonocytic leukemia complicated with immune thrombocytopenia [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(2): 287-290.
[10]	YI Wenjing, FAN Yixuan, QIU Jiatai, FU Xiaoyan, LIU Meifang. Research progress in the role of β-arrestin 1 in the regulation of inflammatory response [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(12): 1593-1600.
[11]	XUAN Zhenquan, CHEN Xuanyi, YAO Zhirong. Research progress in neuroimmune disorders in atopic dermatitis [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(8): 1049-1055.
[12]	WANG Qing, HAN Xiao, ZHANG Xiaobo. Research progress of immune response regulated by epigenetic modification in pneumonia [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(7): 931-938.
[13]	YU Li, SU Xiandu, ZHANG Min, LI Yahui, WANG Le. Construction and validation of prognostic risk model for hepatocellular carcinoma based on biological analysis of palmitoyl-associated enzyme long-chain non-coding RNA [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(6): 747-754.
[14]	HUANG Huayan, XU-ZHANG Wendi, XIA Liliang, YU Yongfeng, LU Shun. Advances in immunotherapy of advanced non-small cell lung cancer with EGFR mutation [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(5): 611-618.
[15]	XU Yidan, ZHANG Qianren, LU Xingyu, DONG Yan. Effect of maternal high-fat diet on placental phenotype in mice [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(4): 397-405.