组蛋白去乙酰化酶SIRT1经Toll样受体4途径对巨噬细胞凋亡的调控

doi:10.6040/j.issn.1671-7554.0.2020.0831

摘要/Abstract

摘要： 目的观察组蛋白去乙酰化酶——人沉默调节蛋白(SIRT1)经组蛋白表观遗传学调控细胞凋亡的具体机制和途径,为动脉粥样硬化防治提出新思路。方法选用假手术组大鼠作为对照,观察颈动脉损伤组大鼠颈动脉组织凋亡、SIRT1、组蛋白3(H3)、H3赖氨酸9位点乙酰化(H3K9Ac)及炎症因子蛋白表达;选用不同条件干预的氧化低密度脂蛋白(oxLDL)暴露巨噬细胞为研究对象,采用细胞功能获得或缺失方法,观察巨噬细胞凋亡、SIRT1、H3、H3K9Ac及炎症因子蛋白表达。结果与假手术组大鼠和对照组巨噬细胞比较,颈动脉损伤组大鼠颈动脉组织和oxLDL暴露巨噬细胞SIRT1蛋白表达减少,H3K9Ac/H3比值增加,Toll样受体4(TLR4)、白介素1β(IL-1β)蛋白表达增加且伴有凋亡增加(P<0.01);与给予SP600125(JNK 通路拮抗剂)、IAXO-102(TLR4通路拮抗剂)、LY294002(PI3K 通路拮抗剂)干预的巨噬细胞比较,IAXO-102干预后,SIRT1减少现象被逆转(P<0.01);给予SIRT1兴奋剂后,巨噬细胞凋亡减轻伴有H3K9Ac/H3比值减少,TLR4、IL-1β蛋白表达减少(P<0.01);给予SIRT1抑制剂后,巨噬细胞凋亡加重伴有H3K9Ac/H3比值增加,TLR4、IL-1β蛋白表达增加(P<0.01)。结论组蛋白乙酰化表观遗传学参与细胞凋亡的调控,进而与动脉粥样硬化发生发展密切相关。组蛋白去乙酰化酶SIRT1减少,H3乙酰化增加,恶化细胞凋亡,促发动脉粥样硬化发生发展,这个过程必经TLR4途径实现。

关键词: 组蛋白表观遗传学, 组蛋白去乙酰化酶, 组蛋白乙酰化失衡, TLR4通路, 巨噬细胞凋亡

Abstract: Objective To observe the mechanism and specific inflammatory pathways of histone deacetylase SIRT1 involved in the regulation of atherosclerosis through histone epigenetics. Methods Rats with high-fat diet and carotid artery injury and oxidized low-density lipoprotein(oxLDL)exposed macrophages under different conditions were selected as the research subjects. Apoptosis, protein expression of SIRT1, histone H3(H3), histone H3 lysine 9-site acetylation(H3K9Ac)and inflammatory factors in rats and macrophages were observed by cells function acquisition or deletion experiments. Results Compared with the control rats and macrophages, rat models with carotid artery injury and oxLDL exposed macrophages had reduced protein expression of SIRT1, increased ratio of H3K9Ac/H3, increased apoptosis, and increased protein expressions of TLR4 and IL-1β(P<0.01). After treatment of SP600125(JNK pathway antagonist), IAXO-102(TLR4 pathway antagonist), LY294002(PI3K pathway antagonist), the phenomenon of SIRT1 reduction was reversed in IAXO-102 intervention macrophages(P<0.01); after treatment of SIRT1 stimulant, apoptosis was reduced accompanied by a decreasing in the ratio of H3K9Ac/H3 and protein expressions of TLR4 and IL-1β(P<0.01). The results were reversed after treatment of SIRT1 inhibitor(P<0.01). Conclusion Histone acetylation epigenetics is involved in the regulation of apoptosis, which is closely related to the occurrence and development of atherosclerosis. Apoptosis is worsened by a decrease in histone deacetylase SIRT1 and an increase in H3 acetylation, which promotes the development of atherosclerosis, and this process must be achieved through the TLR4 signaling pathway.

Key words: Histone epigenetics, Histone deacetylase, Histone acetylation imbalance, TLR4 signaling pathway, Macrophages apoptosis

中图分类号:

R541.4

张晓璐,王丽莉,陈凯明,娄宪芝,张曼. 组蛋白去乙酰化酶SIRT1经Toll样受体4途径对巨噬细胞凋亡的调控[J]. 山东大学学报 (医学版), 2020, 58(12): 8-14.

ZHANG Xiaolu, WANG Lili, CHEN Kaiming, LOU Xianzhi, ZHANG Man. Mechanism of histone deacetylase SIRT1 inhibiting macrophages apoptosis via TLR4 signaling pathway[J]. Journal of Shandong University (Health Sciences), 2020, 58(12): 8-14.

参考文献

[1] 王新, 李春阳, 苏立平, 等. 动脉粥样硬化发病机制及治疗的研究进展[J]. 实用心脑肺血管病杂志, 2017, 25(2): 1-4. WANG Xin, LI Chunyang, SU Liping, et al. Progress on pathogenesis and treatment of atherosclerosis[J]. Practical Journal of Cardiac Cerebral Pneumal and Vascular Disease, 2017, 25(2): 1-4.
[2] Torres Nimbe, Guevara-Cruz Martha, Velázquez-Villegas Laura A, et al. Nutrition and Atherosclerosis[J]. Arch Med Res, 2015, 46(5): 408-426.
[3] Kataoka Masaharu, Wang DZ. Non-coding RNAs including miRNAs and lncRNAs in cardiovascular biology and disease[J]. Cells, 2014, 3(3): 883-898.
[4] Jiang WL, Agrawal D, Boosani C. Cell-specific histone modifications in atherosclerosis(Review)[J]. Mol Med Report, 2018, 18: 1215-1224. doi:10.3892/mmr.2018.9142.
[5] Huang H, Lin S, Garcia BA, et al. Quantitative proteomic analysis of histone modifications[J]. Chem Rev, 2015, 115(6): 2376-2418.
[6] 李双月, 刘淇麒, 冯馨锐, 等. 组蛋白去乙酰化酶3与血管内皮细胞的关系[J]. 吉林医药学院学报, 2018, 39(3): 201-203. LI Shuangyue, LIU Qiqi, FENG Xinrui. et al. Relationship of histone deacetylases 3 and vascular endothelial cells[J]. Journal of Jilin Medical University, 2018, 39(3): 201-203.
[7] 钟磊,师健友,白兰. 组蛋白去乙酰化酶抑制剂JNJ-26481585抗食管癌活性及其作用机制研究[J]. 中国药理学通报, 2019, 35(4): 561-565. ZHONG Lei, SHI Jianyou, BAI Lan. Anti-esophageal cancer activity of JNJ-26481585 and its molecular mechanism[J]. Chinese Pharmacological Bulletin, 2019,35(4): 561-565.
[8] 刘颖, 刘艳秋, 李翠玲, 等. 抑制NLRP3炎症小体中Caspase-1活化对大鼠颈动脉球囊损伤后内膜增生的保护作用[J]. 中山大学学报(医学科学版), 2017, 38(2): 250-253. LIU Ying, LIU Yanqiu, LI Cuiling, et al. Protective effects of inhibiting caspase-1 activation in NLRP3 inflammasome against intimal hyperplasia after balloon injury of carotid artery in rats[J]. Journal of Sun Yat-Sen University(Medical Sciences), 2017, 38(2): 250-253.
[9] 郝阳, 郭晓辰, 张军平. 氧化应激和自噬在动脉粥样硬化中的作用研究新进展[J]. 中国动脉硬化杂志, 2017, 25(4): 404-410. HAO Yang, GUO Xiaochen, ZHANG Junping. The new progress of the role of oxidative stress and autophagy in atherosclerosis[J]. Chinese Journal of Arteriosclerosis, 2017, 25(4): 404-410.
[10] 翁嘉懿, 严金川, 陈瑶, 等. CD137-CD137L信号通路通过活化T细胞核因子c1促进小鼠动脉粥样硬化斑块内血管新生[J]. 中华心血管病杂志, 2016, 44(12): 1040-1046. WENG Jiayi, YAN Jinchuan, CHEN Yao, et al. CD137-CD137L signaling promotes angiogenesis in atherosclerosis plaque of mice through activating nuclear factor of activated T cells c1[J]. Chinese Journal of Cardiology, 2016, 44(12): 1040-1046.
[11] 李亚, 李曙, 马于林, 等. 单核细胞/高密度脂蛋白胆固醇比值与冠心病关系的探讨[J]. 中国心血管病研究, 2019, 17(12): 1110-1114. LI Ya, LI Shu, MA Yulin, et al. Association between monocyte to high-density lipoprotein cholesterol ratio and coronary artery disease[J]. Chinese Journal of Cardiovascular Research, 2019, 17(12): 1110-1114.
[12] 查晴, 曹丽娟, 王燕萍, 等. oxLDL通过TLR4诱导脂质累积和炎症反应促进动脉粥样硬化的分子机制[J]. 上海交通大学学报(医学版), 2017, 37(5): 611-615. ZHA Qing, CAO Lijuan, WANG Yanping, et al. Molecular mechanism of oxLDL inducing lipid accumulation and inflammation in macrophages to promot atherosclerosis via TLR4 signaling pathway[J]. Journal of Shanghai Jiao Tong University(Medical Science), 2017, 37(5): 611-615.
[13] 李闪, 田建伟, 梁立军, 等. 高脂高糖饮食对自发性高血压大鼠水通道蛋白1mRNA表达及对尿钠排泄的影响[J]. 中华老年心脑血管病杂志, 2014, 16(11): 1189-1191. LI Shan, TIAN Jianwei, LIANG Lijun, et al. Effect of high fat and glucose diet on expression of aquaporin-1 mRNA and excretion of urine natrium in spontaneous hypertensive rats[J]. Chinese Journal of Geriatric Heart Brain and Vessel Diseases, 2014, 16(11): 1189-1191.
[14] Fuchs Y, Steller H. Live to Die another way: modes of programmed cell death and the signals emanating from dying cells[J]. Nat Rev Mol Cell Biol, 2015, 16(6): 329-344.
[15] Zhang Y, Qin W, Zhang LY, et al. MicroRNA-26a prevents endothelial cell apoptosis by directly targeting TRPC6 in the setting of atherosclerosis[J]. Sci Rep, 2015, 24(5): 9401.
[16] 刘俊田. 动脉粥样硬化发病的炎症机制的研究进展[J]. 西安交通大学学报(医学版), 2015, 36(2): 141-152. LIU Juntian. Progress in inflammatory pathogenesis of atherosclerosis[J]. Journal of Xian Jiaotong University(Medical Sciences), 2015, 36(2): 141-152.
[17] Waldmann T, Schneider R. Targeting histone modifications-epigenetics in cancer[J]. Curr Opin Cell Biol, 2013, 25(2): 184-189.
[18] Pang MY, Zhuang SG. Histone deacetylase: a potential therapeutic target for fibrotic disorders[J]. J Pharmacol Exp Ther, 2010, 335(2): 266-272.
[19] Blakeslee WW, Wysoczynski CL, Fritz KS, et al. Class I HDAC inhibition stimulates cardiac protein SUMOylation through a post-translational mechanism[J]. Cell Signal, 2014, 26(12): 2912-2920.
[20] Li Z, Martin M, Zhang J, et al. Krüppel-like factor 4 regulation of cholesterol-25-hydroxylase and liver X receptor mitigates atherosclerosis susceptibility[J]. Circulation, 2017, 136(14): 1315-1330.
[21] 王深明, 吴伟滨. 重视动脉粥样硬化相关发病机制的研究[J]. 中华血管外科杂志, 2017, 2(4): 197-200. WANG Shenming, WU Weibin. Pay attention to the research on the pathogenesis of atherosclerosis[J]. Chinese Journal of Vascular Surgery, 2017, 2(4): 197-200.
[22] Zawadzka M, Jagodziński PP. Exercise-induced epigenetic regulations in inflammatory related cells[J]. J Appl Biomed, 2017, 15(1): 63-70.
[23] Rothbart SB, Strahl BD. Interpreting the language of histone and DNA modifications[J]. Biochim Biophys Acta, 2014, 1839(8): 627-643.
[24] Hyun K, Jeon J, Park K, et al. Writing, erasing and reading histone lysine methylations[J]. Exp Mol Med, 2017, 49(4): e324.
[25] 王维, 孟智启, 石放雄. 组蛋白修饰及其生物学效应[J]. 遗传, 2012, 34(7): 19-27. WANG Wei, MENG Zhiqi, SHI Fangxiong. Modification and biological role of histone[J]. Hereditas, 2012, 34(7): 19-27.
[26] 宋博研, 朱卫国. 组蛋白甲基化修饰效应分子的研究进展[J]. 遗传, 2011, 33(4): 285-292. SONG Boyan, ZHU Weiguo. Advances in effector protein of histone methylation[J]. Hereditas, 2011, 33(4): 285-292.
[27] 郭晓强. 组蛋白修饰研究的历程和意义[J]. 科学(上海), 2017, 69(2): 37-41. GUO Xiaoqiang. The history and significance of histone modification[J]. Science, 2017, 69(2): 37-41.
[28] 余益本, 王建平. TLR信号通路研究进展[J]. 细胞与分子免疫学杂志, 2012, 28(12): 1331-1334. YU Yiben, WANG Jianping. Research progress of TLR signal pathway[J]. Chinese Journal of Cellular and Molecular Immunology, 2012, 28(12): 1331-1334.
[29] Guo JX, Liang WQ, Li JH, et al. Knockdown of FSTL1 inhibits oxLDL-induced inflammation responses through the TLR4/MyD88/NF-κB and MAPK pathway[J]. Biochem Biophys Res Commun, 2016, 478(4): 1528-1533.
[30] Ovsepyan VA, Gabdulkhakova AKh, Shubenkiva A, et al. Role of interleukin-10 gene promoter region polymorphism in the development of chronic lymphoid leukemia[J]. Bull Exp Biol Med, 2015, 160(2): 275-277.

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