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p21 gene knockout aggravates radiation-induced heart disease in vivo
Du Haiyang1, Zeng Zhimin1, Xu Peng1, Zhang Peng2, Yi Yali1, Huang Long1, Liu Anwen1
1Department of Oncology, The Second Affiliated Hospital of Nanchang University,Nanchang 330006, China; 2Zhejiang Key Laboratory of Radiation Oncology, Cancer Hospital of University of Chinese Academy of Sciences, Hangzhou 310022, China
AbstractObjective To investigate the role of p21 gene in the radiation-induced heart disease (RIHD) and to evaluate the effect on p21 gene knockout on RIHD phenotype in mouse models. Methods p21-/-mice were utilized in the experimental group, and p21+/-mice were allocated in the control group. RIHD mouse models were established by exposure to 10Gy whole heart irradiation by using a small animal radiation research platform. The heart samples were collected at 6 weeks after irradiation, the gross specimens were measured and subject to HE staining. The wall thickness and left ventricular ejection fraction of the mice were detected by the Vevo2100 ultrasound imaging system. The hypoxia in cardiac tissues was detected by the hypoxia probe method. The apoptosis of cardiac cells was determined by Tunel method. Results Compared with the p21+/-mice, the survival of p21-/-mice was significantly shortened (P=0.004), the interventricular septum was significantly thinned during the diastolic and systolic phases (P=0.049, P=0.006), the left ventricular posterior wall was remarkably thickened (P<0.001) and the left ventricular ejection fraction was significantly decreased (P=0.004). The gross heart tissue was enlarged in the p21-/-mice. HE staining showed the aggregation of inflammatory cells in cardiac tissues and disordered arrangement of myocardial cells. Significant hypoxia and apoptosis could be observed in the p21-/-mouse heart tissues. Conclusions p21-/-mice are prone to more severe RIHD after irradiation, manifested with shortened cardiac survival, weakened cardiac function, abnormal cardiac structure, hypoxia and apoptosis of cardiac tissues. p21 plays an important role in the repair after cardiac irradiation.
Corresponding Authors:
Liu Anwen, Email:awliu666@163.com
Cite this article:
Du Haiyang,Zeng Zhimin,Xu Peng et al. p21 gene knockout aggravates radiation-induced heart disease in vivo[J]. Chinese Journal of Radiation Oncology, 2021, 30(1): 86-89.
Du Haiyang,Zeng Zhimin,Xu Peng et al. p21 gene knockout aggravates radiation-induced heart disease in vivo[J]. Chinese Journal of Radiation Oncology, 2021, 30(1): 86-89.
[1] Baskar R, Lee KA, Yeo R, et al. Cancer and radiation therapy:current advances and future directions[J]. Int J Med Sci, 2012,9(3):193-199. DOI:10.7150/ijms.3635. [2] Marliere S, Vautrin E, Saunier C, et al. Radiation-related heart toxicity:Update in women[J]. Ann Cardiol Angeiol (Paris), 2016,65(6):411-419. DOI:10.1016/j.ancard.2016.10.012. [3] 熊乐,刘安文. 放射性心脏损伤的病理基础及生物学机制[J]. 肿瘤防治研究, 2017, 44(1):66-68. DOI:10.3971/j.issn.1000-8578.2017.01.014. Xiong L, Liu AW. Pathological and biological mechanisms of radiation-induced heart disease[J]. Cancer Res Prev Treat, 2017, 44(1):66-68. 10.3971/j.issn.1000-8578.2017.01.014. [4] Slezak J, Kura B, Babal P, et al. Potential markers and metabolic processes involved in the mechanism of radiation-induced heart injury[J]. Can J Physiol Pharmacol, 2017,95(10):1190-1203. DOI:10.1139/cjpp-2017-0121. [5] Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques[J]. Circulation, 2002, 106(8):927-932. DOI:10.1161/01.cir.0000026393.47805.21. [6] Gao S, Zhao Z, Wu R, et al. Bone marrow mesenchymal stem cell transplantation improves radiation-induced heart injury through DNA damage repair in rat model[J]. Radiat Environ Biophys, 2017, 56(1):63-77. DOI:10.1007/s00411-016-0675-0. [7] Dutto I, Tillhon M, Cazzalini O, et al. Biology of the cell cycle inhibitor P21(CDKN1A):molecular mechanisms and relevance in chemical toxicology[J]. Arch Toxicol, 2015, 89(2):155-178. DOI:10.1007/s00204-014-1430-4. [8] Karimian A, Ahmadi Y, Yousefi B. Multiple functions of P21 in cell cycle, apoptosis and transcriptional regulation after DNA damage[J]. DNA Repair (Amst), 2016, 42(1):63-71. DOI:10.1016/j.dnarep.2016.04.008. [9] Dutto I, Tillhon M, Prosperi E. Assessing cell cycle independent function of the CDK inhibitor P21(CDKN (1) A) in DNA repair[J]. Methods Mol Biol, 2016, 1336(2):123-139. DOI:10.1007/978-1-4939-2926-9_11. [10] Perez-Yepez EA, Saldivar-Ceron HI, Villamar-Cruz O, et al. P21 activated kinase 1:nuclear activity and its role during DNA damage repair[J]. DNA Repair (Amst), 2018, 65(1):42-46. DOI:10.1016/j.dnarep.2018.03.004. [11] Hanova M, Vodickova L, Vaclavikova R, et al. DNA damage, DNA repair rates and mRNA expression levels of cell cycle genes (TP53, P21(CDKN1A), BCL2 and BAX) with respect to occupational exposure to styrene[J]. Carcinogenesis, 2011, 32(1):74-79. DOI:10.1093/carcin/bgq213. [12] 曾小莉. X线及基因沉默对人血管内皮细胞BRCA1、P21表达和细胞周期的影响[D]. 南昌:南昌大学, 2016.Zeng XL. The Effects of X-ray and gene silencing in human vascular endothelial cells:expression of BRCA1 and P21, cell cycle[D]. Nanchang:Nanchang University, 2016. [13] Jermoumi M, Korideck H, Bhagwat M, et al. Comprehensive quality assurance phantom for the small animal radiation research platform (SARRP)[J]. Phys Med, 2015, 31(5):529-535. DOI:10.1016/j.ejmp.2015.04.010. [14] Lee JY, Kim HS, Kim JY, et al. Nuclear translocation of P21(WAF1/CIP1) protein prior to its cytosolic degradation by UV enhances DNA repair and survival[J]. Biochem Biophys Res Commun, 2009, 390(4):1361-1366. DOI:10.1016/j.bbrc.2009.10.160. [15] Soria G, Speroni J, Podhajcer OL, et al. P21 differentially regulates DNA replication and DNA-repair-associated processes after UV irradiation[J]. J Cell Sci, 2008, 121(Pt 19):3271-3282. DOI:10.1242/jcs.027730. [16] Mauro M, Rego MA, Boisvert RA, et al. P21 promotes error-free replication-coupled DNA double-strand break repair[J]. Nucl Acids Res, 2012, 40(17):8348-8360. DOI:10.1093/nar/gks612. [17] Lee CL, Moding EJ, Cuneo KC, et al. P53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice[J]. Sci Signal, 2012, 5(234):a52. DOI:10.1126/scisignal.2002918. [18] Lee YS, Doonan BB, Wu JM, et al. Combined metformin and resveratrol confers protection against UVC-induced DNA damage in A549 lung cancer cells via modulation of cell cycle checkpoints and DNA repair[J]. Oncol Rep, 2016, 35(6):3735-3741. DOI:10.3892/or.2016.4740. [19] Zheng H, Wang S, Zhou P, et al. Effects of ligustrazine on DNA damage and apoptosis induced by irradiation[J]. Environ Toxicol Pharmacol, 2013, 36(3):1197-1206. DOI:10.1016/j.etap.2013.09.023.
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