Journal of Shandong University (Health Sciences) ›› 2022, Vol. 60 ›› Issue (1): 6-12.doi: 10.6040/j.issn.1671-7554.0.2021.0449

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Effects and mechanism of histone deacetylase SIRT1 controlled macrophage apoptosis induced by oxidized low density lipoprotein

LI Hui, JIANG Chaoyang, LIU Yan, ZHANG Man   

  1. Department of Cardiovascular Medicine, Central Hospital Affiliated to Shenyang Medical College, Shenyang 110024, Liaoning, China
  • Published:2022-01-08

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Abstract: Objective To observe the expression of histone H3 lysine residue 9 acetylation(H3K9Ac)in macrophage apoptosis model induced by oxidized low density lipoprotein(oxLDL), and to explore the controlling mechanism of histone deacetylase-inflammatory factor silencing information regulating protein1(SIRT1)on macrophage apoptosis by gene epigenetics, which was realized by peroxisome proliferator activated receptor γ(PPARγ)signaling pathway. Methods Mouse BALB/c macrophage cell line RAW264.7 was cultured with 50 μg/mL oxLDL. The cells were divided into control group(treated with double distilled water)and experimental group(treated with 50 μg/mL oxLDL). The number of apoptotic cells and protein expressions of interleukin(IL-6), SIRT1, H3K9Ac and PPARγ were detected. In addition, the experimental group was treated with SIRT1 stimulant(resveratrol, final concentration 50 nmoL/L)and SIRT1 inhibitor(nicotinamide, final concentration 50 nmoL/L). The apoptosis and protein expressions of SIRT1, H3K9Ac, PPARγ and phosphorylated peroxisome proliferator-activated receptor γ(Ser112 site)［pPPARγ(S112)］ after SIRT1 overexpression or inhibition were detected. The cell apoptosis was detected with Hoechst fluorescence apoptosis staining. The protein expressions of IL-6, SIRT1, H3K9Ac, PPARγ and pPPARγ(S112)were detected with Western blotting. Results The number of apoptotic cells in the experimental group was higher than that in the control group ［(84.88±5.89)vs(7.13±3.31), P<0.01］. The relative protein expressions of IL-6 and H3K9Ac in the experimental group were higher than those in the control group ［(0.50±0.01)vs(0.20±0.02),(0.32±0.02)vs(0.20±0.03), P<0.01］, while the relative protein expressions of SIRT1 and PPARγ in the experimental group were lower than those in the control group ［(0.20±0.01)vs(0.30±0.02),(0.11±0.02)vs(0.20±0.03), P<0.01］. The number of apoptotic cells in the SIRT1 stimulant group was lower than that in the experimental group ［(28.63±6.44)vs(84.88±5.89), P<0.01］, while the number of apoptotic cells in the SIRT1 inhibitor group was higher than that in the experimental group ［(266.88±35.10)vs(84.88±5.89), P<0.01］. In the SIRT1 stimulant group, the relative protein expressions of SIRT1 and PPARγ were higher than those in the experimental group ［(0.27±0.03)vs(0.20±0.01),(0.20±0.02)vs.(0.11±0.02), P<0.01］, while the expressions of H3K9Ac and pPPARγ(S112)were lower ［(0.21±0.02)vs(0.32±0.02),(0.04±0.00)vs(0.12±0.02), P<0.01］. In the SIRT1 inhibitor group, the relative expressions of SIRT1 and PPARγ were lower than those in the experimental group ［(0.10±0.01)vs(0.20±0.01),(0.06±0.01)vs(0.11±0.02), P<0.01］, while the expressions of H3K9Ac and pPPARγ(S112)were higher ［(0.56±0.01)vs(0.32±0.02),(0.18±0.03)vs(0.12±0.02), P<0.01］. Conclusion The gene epigenetics with abnormal histone acetylation modification is involved in the occurrence and development of macrophages apoptosis exposed to oxLDL. In oxLDL-induced macrophage apoptosis model, the expression of histone deacetylase SIRT1 decreases, resulting in a high expression of H3K9Ac, while the downstream PPARγ expressed at a low level and the expression of PPARγ phosphorylation increases. Up-regulation of SIRT1 can reverse the expression of those factors, and improve macrophage apoptosis. SIRT1 has positive regulation on PPARγ signal channel with the anti-inflammatory and anti-apoptosis effects, which are not only related to histone regulating PPARγ expression at gene transcription level, but also to the effects on PPARγ phosphorylation modification after post-translational.

Key words: Gene epigenetics, Histone, Histone deacetylation, Acetylation modification, Peroxisome proliferator activated receptor γ, Apoptosis

CLC Number: 

  • R331.3
[1] Ji YP, Shi TY, Zhang YY, et al. Essential oil from Fructus Alpinia zerumbet(fruit of Alpinia zerumbet(Pers.)Burtt.et Smith)protected against aortic endothelial cell injury and inflammation in vitro and in vivo [J]. J Ethnopharmacol, 2019, 237: 149-158. doi: 10.1016/j.jep.2019.03.011.
[2] GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016 [J]. Lancet, 2017, 390(10100): 1211-1259.
[3] Qi XP, Chen XL, Wang XX. The expression of swiprosin-1 in atherosclerotic tissue and its influence on the apoptosis and the expression of inflammatory factors in macrophages [J]. Chin J Arterioscler, 2018, 26(5): 479-484.
[4] Svoboda P. A toolbox for miRNA analysis [J]. FEBS Lett, 2015, 589(14): 1694-1701.
[5] Schober A, Nazari-Jahantigh M, Weber C. MicroRNA-mediated mechanisms of the cellular stress response in atherosclerosis [J]. Nat Rev Cardiol, 2015, 12(6): 361-374.
[6] 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.
[7] Li H, Li X, Lin H, et al. High HDAC9 is associated with poor prognosis and promotes malignant progression in pancreatic ductal adenocarcinoma [J]. Mol Med Rep, 2020, 21(2): 822-832.
[8] Póciennikowska A, Hromada-Judycka A, Borzcka K, et al. Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling [J]. Cell Mol Life Sci, 2015, 72(3): 557-581.
[9] Lim S, Lee KS, Lee JE, et al. Effect of a new PPARγ agonist, lobeglitazone, on neointimal formation after balloon injury in rats and the development of atherosclerosis [J]. Atherosclerosis, 2015, 243(1): 107-119.
[10] Imai S, Guarente L. NAD+ and sirtuins in aging and disease [J]. Trends Cell Biol, 2014, 24(8): 464-471.
[11] Cai W, Yang T, Liu H, et al. Peroxisome proliferator-activated receptor γ(PPARγ): a master gatekeeper in CNS injury and repair [J]. Prog Neurobiol, 2018, 163/164: 27-58.doi: 10.1016/j.pneurobio.2017.10.002.
[12] Villapol S. Roles of peroxisome proliferator-activated receptor γ on brain and peripheral inflammation [J]. Cell Mol Neurobiol, 2018, 38(1): 121-132.
[13] Han L, Shen WJ, Bittner S, et al. PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part Ⅰ: PPAR-A [J]. Future Cardiol, 2017, 13(3): 259-278.
[14] Krajewski WA. “Direct” and “Indirect” effects of histone modifications: modulation of sterical bulk as a novel source of functionality [J]. Bioessays, 2020, 42(1): e1900136.
[15] Yan X, Pan B, Lv T, et al. Inhibition of histone acetylation by curcumin reduces alcohol-induced fetal cardiac apoptosis [J]. J Biomed Sci, 2017, 24(1): 1.
[16] Huang H, Lin S, Garcia BA, et al. Quantitative proteomic analysis of histone modifications [J]. Chem Rev, 2015, 115(6): 2376-2418.
[17] Hua P, Liu JL, Tao J, et al. Influence of caspase-3 silencing on the proliferation and apoptosis of rat bone marrow mesenchymal stem cells under hypoxia [J]. Int J Exp Med, 2015, 8(2): 1624-1633.
[18] 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.
[19] 李双月, 刘淇麒, 冯馨. 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.
[20] 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.
[21] Jiang X, Ye X, Guo W, et al. Inhibition of HDAC3 promotes ligand-independent PPAR-γ activation by:protein acetylation [J]. J Mol Endocrinol, 2014, 53(2): 191-200.
[22] Li B, Chen MJ, Guo L, et al. Endogenous 2-arachidonoylglycerol alleviates cyclooxygenases-2 elevation-mediated neuronal injury from SO2 inhalation via PPARγ pathway [J]. Toxicol Sci, 2015, 147(2): 535-548.
[23] Mayoral R, Osborn O, McNelis J, et al. Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity [J]. Molecular Metabolism, 2015, 4(5): 378-391.
[24] Qiao L, Guo Z, Bosco C, et al. Maternal high-fat feeding increases placental lipoprotein lipase activity by reducing SIRT1 expression in mice [J]. Diabetes, 2015, 64(9): 3111-3120.
[25] Jang MJ, Ui-Hyun Park, Jeong Woo Kim, et al. CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγ and inhibit adipogenesis [J]. Cell Death Dis, 2017, 8(12): 3201.
[26] Yang F, Melo-Braga MN, Larsen MR, et al. Jorgensen, Giuseppe Palmisano. Battle through signaling between wheat and the fungal pathogen Septoria tritici revealed by proteomics and phosphoproteomics [J]. Mol Cell Proteomics, 2013, 12(9): 2497-2508.
[27] Donnell PE, Ye XZ, DeChellis MA, et al. Lipodystrophy, diabetes and normal serum insulin in PPARγ-deficient neonatal mice [J]. PLoS One, 2016, 11(8): e0160636.
[28] Zhong Q, Zhao S, Yu B, et al. High-density lipoprotein increases the uptake of oxidized low density lipoprotein via PPARγ/CD36 pathway in inflammatory adipocytes [J]. Int J Biol Sci, 2015, 11(3): 256-265.
[29] Tian LF, Wang CG, Michael Gormley, et al. Acetylation-defective mutants of PPARγ is associated with decreased lipid synthesis in breast cancer cells [J]. Oncotarget, 2014, 5(17): 7303-7315.
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