XRCC3 polymorphism is associated with hypertension-induced left ventricular hypertrophy

Abstract

Deficiency of X-ray repair cross-complementing protein 3 (XRCC3), a DNA-damage repair molecule, and the 241Met variant of XRCC3 have been reported to increase endoreduplication, which induces polyploidy. The aims of this study were to determine the impact of the XRCC3 polymorphism on the incidence of hypertension-induced left ventricular hypertrophy (LVH) and to investigate the mechanisms underlying any potential relationship. Patients undergoing chronic hemodialysis (n = 77) were genotyped to assess for the XRCC3 Thr241Met polymorphism. The XRCC3 241Thr/Met genotype was more frequent in the LVH (+) group than in the LVH (−) group (42.3 vs. 13.7%, χ2 = 7.85, p = 0.0051). To investigate possible mechanisms underlying these observations, human XRCC3 cDNA of 241Thr or that of 241Met was introduced into cultured CHO cells. The surface area of CHO cells expressing XRCC3 241Met was larger than that expressing 241Thr. Spontaneous DNA double-strand breaks accumulated to a greater degree in NIH3T3 cells expressing 241Met (3T3-241Met) than in those expressing 241Thr (3T3-241Thr). DNA damage caused by radiation induced cell senescence more frequently in 3T3-241Met. The levels of basal and TNF-α-stimulated MCP-1 mRNA and protein secretion were higher in 3T3-241Met. Finally, FACS analysis revealed that the cell percentage in G2/M phase including polyploidy was significantly higher in 3T3-241Met than in 3T3-241Thr. Furthermore, the basal level of MCP-1 mRNA positively correlated with the cell percentage in G2/M phase and polyploidy. These data suggest that the XRCC3 241Met increases the risk of LVH via accumulation of DNA damage, thereby altering cell cycle progression and inducing cell senescence and a proinflammatory phenotype.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Katholi RE, Couri DM. Left ventricular hypertrophy: major risk factor in patients with hypertension: update and practical clinical applications. Int J Hypertens. 2011;2011:495349.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Bella JN, Goring HH. Genetic epidemiology of left ventricular hypertrophy. Am J Cardiovasc Dis. 2012;2:267–78.

    PubMed  PubMed Central  CAS  Google Scholar 

  3. 3.

    Yoshihara T, Ishida M, Kinomura A, Katsura M, Tsuruga T, Tashiro S, Asahara T, Miyagawa K. XRCC3 deficiency results in a defect in recombination and increased endoreduplication in human cells. EMBO J. 2004;23:670–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. 4.

    David-Beabes GL, Lunn RM, London SJ. No association between the XPD (Lys751G1n) polymorphism or the XRCC3 (Thr241Met) polymorphism and lung cancer risk. Cancer Epidemiol Biomark Prev. 2001;10:911–2.

    CAS  Google Scholar 

  5. 5.

    McFarland TM, Alam M, Goldstein S, Pickard SD, Stein PD. Echocardiographic diagnosis of left ventricular hypertrophy. Circulation. 1978;57:1140–4.

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Wanner C, Amann K, Shoji T. The heart and vascular system in dialysis. Lancet. 2016;388:276–84.

    Article  PubMed  Google Scholar 

  7. 7.

    Ok E, Asci G, Chazot C, Ozkahya M, Mees EJ. Controversies and problems of volume control and hypertension in haemodialysis. Lancet . 2016;388:185–93.

    Article  Google Scholar 

  8. 8.

    Watanabe S, Kawamoto S, Ohtani N, Hara E. Impact of senescence-associated secretory phenotype and its potential as a therapeutic target for senescence-associated diseases. Cancer Sci. 2017;108:563–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. 9.

    Bei L, Xiao-Dong T, Yu-Fang G, Jian-Ping S, Zhao-Yu Y. DNA repair gene XRCC3 Thr241Met polymorphisms and lung cancer risk: a meta-analysis. Bull Cancer. 2015;102:332–9.

    Article  PubMed  Google Scholar 

  10. 10.

    Perez-Ramirez C, Canadas-Garre M, Molina MA, Robles AI, Faus-Dader MJ, Calleja-Hernandez MA. Contribution of genetic factors to platinum-based chemotherapy sensitivity and prognosis of non-small cell lung cancer. Mutat Res. 2017;771:32–58.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Qin XP, Zhou Y, Chen Y, Li NN, Wu XT. XRCC3 Thr241Met polymorphism and gastric cancer susceptibility: a meta-analysis. Clin Res Hepatol Gastroenterol. 2014;38:226–34.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Johmura Y, Shimada M, Misaki T, Naiki-Ito A, Miyoshi H, Motoyama N, Ohtani N, Hara E, Nakamura M, Morita A, Takahashi S, Nakanishi M. Necessary and sufficient role for a mitosis skip in senescence induction. Mol Cell. 2014;55:73–84.

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Engelmann GL, Vitullo JC, Gerrity RG. Age-related changes in ploidy levels and biochemical parameters in cardiac myocytes isolated from spontaneously hypertensive rats. Circ Res. 1986;58:137–47.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Frieler RA, Mortensen RM. Immune cell and other noncardiomyocyte regulation of cardiac hypertrophy and remodeling. Circulation . 2015;131:1019–30.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    van Vuren EJ, Malan L, von Kanel R, Cockeran M, Malan NT. Hyperpulsatile pressure, systemic inflammation and cardiac stress are associated with cardiac wall remodeling in an African male cohort: the SABPA study. Hypertens Res. 2016;39:648–53.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Kuwahara F, Kai H, Tokuda K, Takeya M, Takeshita A, Egashira K, Imaizumi T. Hypertensive myocardial fibrosis and diastolic dysfunction: another model of inflammation? Hypertension. 2004;43:739–45.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Johmura Y, Yamashita E, Shimada M, Nakanishi K, Nakanishi M. Defective DNA repair increases susceptibility to senescence through extension of Chk1-mediated G2 checkpoint activation. Sci Rep. 2016;6:31194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. 18.

    Nakayama Y, Yamaguchi N. Role of cyclin B1 levels in DNA damage and DNA damage-induced senescence. Int Rev Cell Mol Biol. 2013;305:303–37.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Oren Traub for editing this manuscript. Part of this work was performed at the Analysis Center of Life Science, Natural Science Center for Basic Research and Development, and the Joint Usage/Research Center (RIRBM), Hiroshima University. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKENHI#15K09122 to MI and KAKENHI#17K10449 to TI), research grants from the Takeda Science Foundation (http://www.takeda-sci.or.jp/index.html) to MI, the SENSHIN Medical Research Foundation (http://www.mt-pharma.co.jp/zaidan/) to MI and the program of the network-type joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University, Nagasaki University, and Fukushima Medical University. Dr. Ariyandy was financially supported by the Directorate General of Resources for Research, Technology & Higher Education (DG-RSTHE), Indonesia.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Mari Ishida.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ariyandy, A., Sakai, C., Ishida, M. et al. XRCC3 polymorphism is associated with hypertension-induced left ventricular hypertrophy. Hypertens Res 41, 426–434 (2018). https://doi.org/10.1038/s41440-018-0038-0

Download citation