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电离辐射(ionizing radiation,IR)是指波长短、频率高、能量高的射线或粒子与物质作用引起电离的辐射。其可通过直接或间接作用引起生物辐射性损伤[1]。近年来IR广泛应用于X射线检查、CT检查、肿瘤治疗和介入治疗等工业和医疗领域。众所周知,肿瘤患者在接受局部放疗时,射线会对肿瘤组织远端的正常组织产生影响,诱发疾病,如乳腺癌患者和霍奇金淋巴瘤患者在高剂量放疗后期会出现辐射诱发的心血管疾病[2-3];头颈部肿瘤患者接受放疗后,中风风险增加[4];IR还会促进与老化相关的神经退行性疾病的发展等[5-6]。血管内皮细胞(vascular endothelial cells,VEC)对IR敏感,是位于血液与血管壁之间的单层扁平细胞,它不仅是血液和组织之间的保护屏障,也是内分泌细胞。在控制血管张力和血液流动性、维持凝血和纤溶之间的平衡、调节免疫反应和血管生成等方面发挥着重要的作用[7]。
Bautista-Niño等[8]的研究结果表明,IR可诱导VEC衰老,而VEC衰老会导致心血管功能障碍,诱发心血管疾病[9-10],我们对IR诱导VEC衰老的特征、作用机制以及可能诱发的相关疾病等方面进行简要综述,并简单对非编码RNA在IR诱导VEC衰老方面的研究进行展望。
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细胞衰老是指细胞经过有限的分裂次数后,进入不可逆、永久性的细胞周期停滞,但仍可保持代谢和转录活性。根据其发生机制可分为复制性细胞衰老和应激性细胞衰老两类[11]。IR可通过氧化应激和DNA损伤诱导细胞发生应激性衰老。不同剂量的IR均可诱导VEC衰老(表1),由表1可知,IR在体内外均可诱导VEC衰老,人脐静脉内皮细胞为常用的实验材料,多数研究集中在单次高剂量照射处理,有少数研究是以低剂量照射或多次累积照射处理。
序号 实验材料 射线类型 总剂量(剂量率) 主要发现 研究者 1 HBMVEC γ射线 4 Gy
(3.81 Gy/min)PGC1α乙酰化是IR诱导VEC衰老的重要
因素Kim等[5] 7周龄雄性C57BL/6
小鼠X射线 8 Gy 2 bEnd.3 X射线 20 Gy IR诱导脑微VEC衰老 McRobb等[6] 3 HUVEC γ射线 0.69、2.07、4.13 Gy
(4.1 mGy/h)慢性低剂量率γ射线可诱导HUVEC衰老 Yentrapalli等[12] 4 大鼠肾小球内皮细胞 X射线 20 Gy
(4.96 Gy/min)IR诱导肾小球VEC衰老,IL-6为主要SASP Aratani等[13] 7~8周龄雄性Dark
Agti大鼠X射线 18 Gy
(1.34 Gy/min)5 HUVEC γ射线 4 Gy
(2.82 Gy/min)IGFBP5参与IR诱导的衰老 Kim等[14] 6 TICAE X射线 0.05、0.1、0.5、2 Gy
(0.5 Gy/min)IR诱导VEC衰老,且IL-6和CCL2的表达水平
增加Baselet等[15] 7 HCAEC X射线 0.5 Gy
(0.5 Gy/min)IR诱导HCAEC衰老,且p16和p21的表达水平
显著增加Azimzadeh等[16] 8 HUVEC X射线 8、15 Gy IR通过TGF-BRI/ALK5抑制血管生成 Imaizumi等[17] 9 HAEC − 4 Gy GDF15通过ROS介导的p16途径参与IR诱导的HAEC衰老 Park等[18] 10 HUVEC X射线 0~8 Gy
(1.3 Gy/min)维生素D通过调节MAPK/SIRT1信号通路抑制HUVEC衰老 Marampon等[19] 11 HUVEC γ射线 0.2 Gy Ku86抑制低剂量IR诱导的HUVEC衰老和凋亡 Wu等[20] 12 HUVEC γ射线 4.032 Gy
(2.4 mGy/h)PI3K/AKT/mTOR通路与IR诱导的细胞衰老
相关Yentrapalli等[21] 13 HPAEC X射线 10 Gy
(2.4 Gy/min)IGF-1R是IR诱导细胞衰老的关键调节因子 Panganiban等[22] 14 HUVEC γ射线 2.066、4.133 Gy
(4.1 mGy/h)4.1 mGy/h照射的HUVEC衰老,且IGFBP5
参与IR诱导的衰老Rombouts等[23] 15 HBMVEC γ射线 4 Gy
(3.5 Gy/min)CXCR4和SDF-1在体内外均可抑制辐射诱导
的内皮细胞衰老Heo等[24] 7周龄雌性C57BL/6
和BALB/c裸鼠X射线 8 Gy
(2 Gy/min)16 HUVEC γ射线 2、4、8 Gy
(2 Gy/min)IR通过DSB/NEMO/NF-кB信号通路诱导VEC
衰老Dong等[25] 17 HMVEC-L X射线 15 Gy p53和O2·−/Cplx Ⅱ参与IR诱导的VEC衰老 Lafargue等[26] 18 HUVEC和HMVEC γ射线 10 Gy 微小RNA-494和微小RNA-99b通过MRN复
合物抑制DNA修复,导致细胞衰老Espinosa-Diez等[27] 19 TICAE X射线 10 Gy CD44启动子在IR诱导的衰老内皮细胞中起着重要的作用 Lowe等[28] 注:HBMVEC为人脑部微血管内皮细胞;bEnd.3为小鼠脑微血管内皮细胞系;HUVEC为人脐静脉内皮细胞;TICAE为端粒酶永生化的人冠状动脉内皮细胞;HCAEC为人冠状动脉内皮细胞;HAEC为人主动脉内皮细胞;HPAEC为人肺动脉内皮细胞;HBMVEC为人脑部微血管内皮细胞;HMVEC-L为人肺微血管内皮细胞;PGC1α为过氧化物酶体增殖物激活受体γ辅激活因子1α;VEC为血管内皮细胞;IL-6为白细胞介素6;SASP为衰老相关的分泌表型;IGFBP5为胰岛素样生长因子结合蛋白5;CCL2为趋化因子2;TGF-BRI为转化生长因子Ⅰ型受体;ALK5为激活素受体样酶5;GDF15为生长分化因子15;ROS为活性氧;MAPK为丝裂原活化蛋白激酶;SIRT1为沉默信息调节因子2相关酶1;Ku86为参与非同源末端连接过程的一个关键分子;PI3K为磷脂酰肌醇-3-激酶;AKT为蛋白激酶 B;mTOR为雷帕霉素靶蛋白;IGF1R为胰岛素样生长因子1受体;CXCR4为CXC趋化因子受体4;SDF-1为基质细胞衍生因子1;DSB为DNA双链断裂;NEMO为NF-κB必须调节蛋白;NF-кB为核因子кB;O2ˑ−为超氧阴离子自由基;MRN为MRE11a-Rad50-Nbs1复合物;Cplx Ⅱ为线粒体呼吸复合物Ⅱ;CD44为一种膜整合蛋白;−为无此项内容 表 1 电离辐射诱导血管内皮细胞衰老的研究
Table 1. Research on the senescence of vascular endothelial cells induced by ionizing radiation
IR诱导的VEC发生的应激性衰老会表现出多种衰老表型(图1)。(1)在细胞形态上与复制性衰老表现一致,均表现为细胞扁平且宽大,细胞核和核仁体积增大[12]。(2)衰老的VEC会分泌许多炎症介质(细胞因子、趋化因子和生长因子等)和细胞外蛋白酶[白细胞介素(interleukin,IL)1、IL-6、IL-8、趋化因子2、TNF-α、转化生长因子β、纤溶酶原激活物抑制剂1、血管细胞黏附分子1和细胞间黏附分子1等][12-13, 14-16],称为衰老相关的分泌表型(senescence-associated secretory phenotype,SASP)。除此以外,常见的表现还有活性氧(reactive oxygen species,ROS)产生增加、衰老相关半乳糖苷酶及与肿瘤抑制作用相关的基因(如p16、p53和p21)表达水平增加;NO生成减少、Ki-67(细胞增殖核抗原)和血栓调节蛋白减少;细胞周期阻滞和血管生成功能受损等[12-13, 16]。
电离辐射诱导血管内皮细胞衰老的研究进展
Research progress on vascular endothelial cell senescence induced by ionizing radiation
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摘要: 血管内皮细胞(VEC)是位于动脉、静脉和毛细血管内层的单层扁平细胞,对电离辐射(IR)非常敏感。IR不仅可以诱导VEC凋亡还可以诱导其衰老。衰老的VEC表现出多种表型,导致内皮功能障碍。笔者对IR诱导VEC衰老的特征及其相关作用机制和IR诱导衰老VEC在血管疾病中的作用进行综述。Abstract: Vascular endothelial cells (VEC), a single layer of flat cells lines the arteries, veins and capillaries, are sensitive to ionizing radiation (IR). IR is able to induce apoptosis and senescence in VEC. Senescent VEC shows a variety of senescent phenotypes, which further result in endothelial dysfunction. This paper reviews the characteristic of IR-induced VEC senescence, as well as its related functional mechanisms by which IR-induced senescent VEC plays a role in vascular diseases.
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Key words:
- Radiation, ionizing /
- Endothelial cells /
- Cellular senescence /
- Vascular diseases
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表 1 电离辐射诱导血管内皮细胞衰老的研究
Table 1. Research on the senescence of vascular endothelial cells induced by ionizing radiation
序号 实验材料 射线类型 总剂量(剂量率) 主要发现 研究者 1 HBMVEC γ射线 4 Gy
(3.81 Gy/min)PGC1α乙酰化是IR诱导VEC衰老的重要
因素Kim等[5] 7周龄雄性C57BL/6
小鼠X射线 8 Gy 2 bEnd.3 X射线 20 Gy IR诱导脑微VEC衰老 McRobb等[6] 3 HUVEC γ射线 0.69、2.07、4.13 Gy
(4.1 mGy/h)慢性低剂量率γ射线可诱导HUVEC衰老 Yentrapalli等[12] 4 大鼠肾小球内皮细胞 X射线 20 Gy
(4.96 Gy/min)IR诱导肾小球VEC衰老,IL-6为主要SASP Aratani等[13] 7~8周龄雄性Dark
Agti大鼠X射线 18 Gy
(1.34 Gy/min)5 HUVEC γ射线 4 Gy
(2.82 Gy/min)IGFBP5参与IR诱导的衰老 Kim等[14] 6 TICAE X射线 0.05、0.1、0.5、2 Gy
(0.5 Gy/min)IR诱导VEC衰老,且IL-6和CCL2的表达水平
增加Baselet等[15] 7 HCAEC X射线 0.5 Gy
(0.5 Gy/min)IR诱导HCAEC衰老,且p16和p21的表达水平
显著增加Azimzadeh等[16] 8 HUVEC X射线 8、15 Gy IR通过TGF-BRI/ALK5抑制血管生成 Imaizumi等[17] 9 HAEC − 4 Gy GDF15通过ROS介导的p16途径参与IR诱导的HAEC衰老 Park等[18] 10 HUVEC X射线 0~8 Gy
(1.3 Gy/min)维生素D通过调节MAPK/SIRT1信号通路抑制HUVEC衰老 Marampon等[19] 11 HUVEC γ射线 0.2 Gy Ku86抑制低剂量IR诱导的HUVEC衰老和凋亡 Wu等[20] 12 HUVEC γ射线 4.032 Gy
(2.4 mGy/h)PI3K/AKT/mTOR通路与IR诱导的细胞衰老
相关Yentrapalli等[21] 13 HPAEC X射线 10 Gy
(2.4 Gy/min)IGF-1R是IR诱导细胞衰老的关键调节因子 Panganiban等[22] 14 HUVEC γ射线 2.066、4.133 Gy
(4.1 mGy/h)4.1 mGy/h照射的HUVEC衰老,且IGFBP5
参与IR诱导的衰老Rombouts等[23] 15 HBMVEC γ射线 4 Gy
(3.5 Gy/min)CXCR4和SDF-1在体内外均可抑制辐射诱导
的内皮细胞衰老Heo等[24] 7周龄雌性C57BL/6
和BALB/c裸鼠X射线 8 Gy
(2 Gy/min)16 HUVEC γ射线 2、4、8 Gy
(2 Gy/min)IR通过DSB/NEMO/NF-кB信号通路诱导VEC
衰老Dong等[25] 17 HMVEC-L X射线 15 Gy p53和O2·−/Cplx Ⅱ参与IR诱导的VEC衰老 Lafargue等[26] 18 HUVEC和HMVEC γ射线 10 Gy 微小RNA-494和微小RNA-99b通过MRN复
合物抑制DNA修复,导致细胞衰老Espinosa-Diez等[27] 19 TICAE X射线 10 Gy CD44启动子在IR诱导的衰老内皮细胞中起着重要的作用 Lowe等[28] 注:HBMVEC为人脑部微血管内皮细胞;bEnd.3为小鼠脑微血管内皮细胞系;HUVEC为人脐静脉内皮细胞;TICAE为端粒酶永生化的人冠状动脉内皮细胞;HCAEC为人冠状动脉内皮细胞;HAEC为人主动脉内皮细胞;HPAEC为人肺动脉内皮细胞;HBMVEC为人脑部微血管内皮细胞;HMVEC-L为人肺微血管内皮细胞;PGC1α为过氧化物酶体增殖物激活受体γ辅激活因子1α;VEC为血管内皮细胞;IL-6为白细胞介素6;SASP为衰老相关的分泌表型;IGFBP5为胰岛素样生长因子结合蛋白5;CCL2为趋化因子2;TGF-BRI为转化生长因子Ⅰ型受体;ALK5为激活素受体样酶5;GDF15为生长分化因子15;ROS为活性氧;MAPK为丝裂原活化蛋白激酶;SIRT1为沉默信息调节因子2相关酶1;Ku86为参与非同源末端连接过程的一个关键分子;PI3K为磷脂酰肌醇-3-激酶;AKT为蛋白激酶 B;mTOR为雷帕霉素靶蛋白;IGF1R为胰岛素样生长因子1受体;CXCR4为CXC趋化因子受体4;SDF-1为基质细胞衍生因子1;DSB为DNA双链断裂;NEMO为NF-κB必须调节蛋白;NF-кB为核因子кB;O2ˑ−为超氧阴离子自由基;MRN为MRE11a-Rad50-Nbs1复合物;Cplx Ⅱ为线粒体呼吸复合物Ⅱ;CD44为一种膜整合蛋白;−为无此项内容 -
[1] Soloviev AI, Kizub IV. Mechanisms of vascular dysfunction evoked by ionizing radiation and possible targets for its pharmacological correction[J]. Biochem Pharmacol, 2019, 159: 121−139. DOI: 10.1016/j.bcp.2018.11.019. [2] Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-term survivors of Hodgkin's disease treated with chest radiotherapy[J]. J Clin Oncol, 2004, 22(15): 3139−3148. DOI: 10.1200/JCO.2004.09.109. [3] Darby SC, McGale P, Taylor CW, et al. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300 000 women in US SEER cancer registries[J]. Lancet Oncol, 2005, 6(8): 557−565. DOI: 10.1016/S1470-2045(05)70251-5. [4] Wethal T, Nedregaard B, Andersen R, et al. Atherosclerotic lesions in lymphoma survivors treated with radiotherapy[J]. Radiother Oncol, 2014, 110(3): 448−454. DOI: 10.1016/j.radonc.2013.10.029. [5] Kim SB, Heo JI, Kim H, et al. Acetylation of PGC1α by histone deacetylase 1 downregulation is implicated in radiation-induced senescence of brain endothelial cells[J]. J Gerontol A Biol Sci Med Sci, 2019, 74(6): 787−793. DOI: 10.1093/gerona/gly167. [6] McRobb LS, McKay MJ, Gamble JR, et al. Ionizing radiation reduces ADAM10 expression in brain microvascular endothelial cells undergoing stress-induced senescence[J/OL]. Aging, 2017, 9(4): 1248−1268[2020-06-29]. https://www.aging-us.com/article/101225/text. DOI: 10.18632/aging.101225. [7] Krüger-Genge A, Blocki A, Franke RP, et al. Vascular endothelial cell biology: an update[J/OL]. Int J Mol Sci, 2019, 20(18): 4411[2020-06-29]. https://www.mdpi.com/1422-0067/20/18/4411. DOI: 10.3390/ijms20184411. [8] Bautista-Niño PK, Portilla-Fernandez E, Vaughan DE, et al. DNA damage: a main determinant of vascular aging[J/OL]. Int J Mol Sci, 2016, 17(5): 748[2020-06-29]. https://www.mdpi.com/1422-0067/17/5/748. DOI: 10.3390/ijms17050748. [9] Minamino T, Miyauchi H, Yoshida T, et al. Endothelial cell senescence in human atherosclerosis: role of telomeres in endothelial dysfunction[J]. J Cardiol, 2003, 41(1): 39−40. [10] Kurz DJ, Decary S, Hong Y, et al. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells[J]. J Cell Sci, 2004, 117(11): 2417−2426. DOI: 10.1242/jcs.01097. [11] Gorgoulis V, Adams PD, Alimonti A, et al. Cellular senescence: defining a path forward[J]. Cell, 2019, 179(4): 813−827. DOI: 10.1016/j.cell.2019.10.005. [12] Yentrapalli R, Azimzadeh O, Barjaktarovic Z, et al. Quantitative proteomic analysis reveals induction of premature senescence in human umbilical vein endothelial cells exposed to chronic low-dose rate gamma radiation[J]. Proteomics, 2013, 13(7): 1096−1107. DOI: 10.1002/pmic.201200463. [13] Aratani S, Tagawa M, Nagasaka S, et al. Radiation-induced premature cellular senescence involved in glomerular diseases in rats[J/OL]. Sci Rep, 2018, 8(1): 16812[2020-06-29]. https://www.nature.com/articles/s41598-018-34893-8. DOI: 10.1038/s41598-018-34893-8. [14] Kim KS, Kim JE, Choi KJ, et al. Characterization of DNA damage-induced cellular senescence by ionizing radiation in endothelial cells[J]. Int J Radiat Biol, 2014, 90(1): 71−80. DOI: 10.3109/09553002.2014.859763. [15] Baselet B, Belmans N, Coninx E, et al. Functional gene analysis reveals cell cycle changes and inflammation in endothelial cells irradiated with a single X-ray dose[J/OL]. Front Pharmacol, 2017, 8: 213[2020-06-29]. https://www.frontiersin.org/articles/10.3389/fphar.2017.00213/full. DOI: 10.3389/fphar.2017.00213. [16] Azimzadeh O, Subramanian V, Ständer S, et al. Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways[J]. Int J Radiat Biol, 2017, 93(9): 920−928. DOI: 10.1080/09553002.2017.1339332. [17] Imaizumi N, Monnier Y, Hegi M, et al. Radiotherapy suppresses angiogenesis in mice through TGF-βRI/ALK5-dependent inhibition of endothelial cell sprouting[J/OL]. PLoS One, 2010, 5(6): e11084[2020-06-29]. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011084. DOI: 10.1371/journal.pone.0011084. [18] Park H, Kim CH, Jeong JH, et al. GDF15 contributes to radiation-induced senescence through the ROS-mediated p16 pathway in human endothelial cells[J/OL]. Oncotarget, 2016, 7(9): 9634−9644[2020-06-29]. https://www.oncotarget.com/article/7457/text. DOI: 10.18632/oncotarget.7457. [19] Marampon F, Gravina GL, Festuccia C, et al. Vitamin D protects endothelial cells from irradiation-induced senescence and apoptosis by modulating MAPK/SirT1 axis[J]. J Endocrinol Invest, 2016, 39(4): 411−422. DOI: 10.1007/s40618-015-0381-9. [20] Wu K, Chen ZJ, Peng Q, et al. Ku86 alleviates human umbilical vein endothelial cellular apoptosis and senescence induced by a low dose of ionizing radiation[J]. J Int Med Res, 2019, 47(2): 893−904. DOI: 10.1177/0300060518805302. [21] Yentrapalli R, Azimzadeh O, Sriharshan A, et al. The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation[J/OL]. PLoS One, 2013, 8(8): e70024[2020-06-29]. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070024. DOI: 10.1371/journal.pone.0070024. [22] Panganiban RAM, Day RM. Inhibition of IGF-1R prevents ionizing radiation-induced primary endothelial cell senescence[J/OL]. PLoS One, 2013, 8(10): e78589[2020-06-29]. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078589. DOI: 10.1371/journal.pone.0078589. [23] Rombouts C, Aerts A, Quintens R, et al. Transcriptomic profiling suggests a role for IGFBP5 in premature senescence of endothelial cells after chronic low dose rate irradiation[J]. Int J Radiat Biol, 2014, 90(7): 560−574. DOI: 10.3109/09553002.2014.905724. [24] Heo JI, Kim KI, Woo SK, et al. Stromal cell-derived factor 1 protects brain vascular endothelial cells from radiation-induced brain damage[J/OL]. Cells, 2019, 8(10): 1230[2020-06-29]. https://www.mdpi.com/2073-4409/8/10/1230. DOI: 10.3390/cells8101230. [25] Dong XR, Tong F, Qian C, et al. NEMO modulates radiation-induced endothelial senescence of human umbilical veins through NF-κB signal pathway[J]. Radiat Res, 2015, 183(1): 82−93. DOI: 10.1667/RR13682.1. [26] Lafargue A, Degorre C, Corre I, et al. Ionizing radiation induces long-term senescence in endothelial cells through mitochondrial respiratory complex Ⅱ dysfunction and superoxide generation[J]. Free Radic Biol Med, 2017, 108: 750−759. DOI: 10.1016/j.freeradbiomed.2017.04.019. [27] Espinosa-Diez C, Wilson R, Chatterjee N, et al. MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling[J/OL]. Cell Death Dis, 2018, 9(6): 632[2020-06-29]. https://www.nature.com/articles/s41419-018-0690-y. DOI: 10.1038/s41419-018-0690-y. [28] Lowe D, Raj K. Premature aging induced by radiation exhibits pro-atherosclerotic effects mediated by epigenetic activation of CD44 expression[J]. Aging Cell, 2014, 13(5): 900−910. DOI: 10.1111/acel.12253. [29] Taunk NK, Haffty BG, Kostis JB, et al. Radiation-induced heart disease: pathologic abnormalities and putative mechanisms[J/OL]. Front Oncol, 2015, 5: 39[2020-06-29]. https://www.frontiersin.org/articles/10.3389/fonc.2015.00039/full. DOI: 10.3389/fonc.2015.00039. [30] Ungvari Z, Podlutsky A, Sosnowska D, et al. Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular raDIOsensitivity[J]. J Gerontol A Biol Sci Med Sci, 2013, 68(12): 1443−1457. DOI: 10.1093/gerona/glt057.