Top

Published in:

Open Access 01-03-2018 | Original Article

Heart irradiation reduces microvascular density and accumulation of HSPA1 in mice

Authors: Anna Walaszczyk, Katarzyna Szołtysek, Karol Jelonek, Joanna Polańska, Wolfgang Dörr, Julia Haagen, Piotr Widłak, Dorota Gabryś, PhD, MD

Published in: Strahlentherapie und Onkologie | Issue 3/2018

Abstract

Purpose

Improvement of radiotherapy techniques reduces the exposure of normal tissues to ionizing radiation. However, the risk of radiation-related late effects remains elevated. In the present study, we investigated long-term effects of radiation on heart muscle morphology.

Materials and methods

We established a mouse model to study microvascular density (MVD), deposition of collagen fibers, and changes in accumulation of heat shock 70 kDa protein 1 (HSPA1) in irradiated heart tissue. Hearts of C57BL/6 mice received a single dose of X‑ray radiation in the range 0.2–16 Gy. Analyses were performed 20, 40, and 60 weeks after irradiation.

Results

Reduction in MD was revealed as a long-term effect observed 20–60 weeks after irradiation. Moreover, a significant and dose-dependent increase in accumulation of HSPA1, both cytoplasmic and nuclear, was observed in heart tissues collected 20 weeks after irradiation. We also noticed an increase in collagen deposition in hearts treated with higher doses.

Conclusions

This study shows that some changes induced by radiation in the heart tissue, such as reduction in microvessel density, increase in collagen deposition, and accumulation of HSPA1, are observed as long-term effects which might be associated with late radiation cardiotoxicity.

Available only for authorised users

Marmagkiolis K, Finch W, Tsitlakidou D, Josephs T, Iliescu C, Best JF, Yang EH (2016) Radiation toxicity to the cardiovascular system. Curr Oncol Rep 18(3):15. https://doi.org/10.1007/s11912-016-0502-4 CrossRefPubMed

Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, Correa C, Cutter D, Gagliardi G, Gigante B, Jensen MB, Nisbet A, Peto R, Rahimi K, Taylor C, Hall P (2013) Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 368(11):987–998. https://doi.org/10.1056/NEJMoa1209825 CrossRefPubMed

Trott KR (2016) Some considerations for future research into the risks of radiation-induced cardiovascular diseases. Strahlenther Onkol 192(11):747–749. https://doi.org/10.1007/s00066-016-1030-8 CrossRefPubMed

Taylor CW, Wang Z, Macaulay E, Jagsi R, Duane F, Darby SC (2015) Exposure of the heart in breast cancer radiation therapy: A systematic review of heart doses published during 2003 to 2013. Int J Radiat Oncol Biol Phys 93(4):845–853. https://doi.org/10.1016/j.ijrobp.2015.07.2292 CrossRefPubMed

Tapio S (2016) Pathology and biology of radiation-induced cardiac disease. J Radiat Res 57(5):439–448. https://doi.org/10.1093/jrr/rrw064 CrossRefPubMedPubMedCentral

Cardiorisk (2017) Cardiorisk. http://www.cardiorisk.eu/. Accessed 10 Aug 2017

Boerma M, Hauer-Jensen M (2010) Potential targets for intervention in radiation-induced heart disease. Curr Drug Targets 11(11):1405–1412CrossRefPubMedPubMedCentral

Andratschke N, Maurer J, Molls M, Trott KR (2011) Late radiation-induced heart disease after radiotherapy. Clinical importance, radiobiological mechanisms and strategies of prevention. Radiother Oncol 100(2):160–166. https://doi.org/10.1016/j.radonc.2010.08.010 CrossRefPubMed

Gabrys D, Greco O, Patel G, Prise KM, Tozer GM, Kanthou C (2007) Radiation effects on the cytoskeleton of endothelial cells and endothelial monolayer permeability. Int J Radiat Oncol Biol Phys 69(5):1553–1562. https://doi.org/10.1016/j.ijrobp.2007.08.039 CrossRefPubMed

10.

Darby SC, Cutter DJ, Boerma M, Constine LS, Fajardo LF, Kodama K, Mabuchi K, Marks LB, Mettler FA, Pierce LJ, Trott KR, Yeh ET, Shore RE (2010) Radiation-related heart disease: Current knowledge and future prospects. Int J Radiat Oncol Biol Phys 76(3):656–665. https://doi.org/10.1016/j.ijrobp.2009.09.064 CrossRefPubMedPubMedCentral

11.

Taunk NK, Haffty BG, Kostis JB, Goyal S (2015) Radiation-induced heart disease: Pathologic abnormalities and putative mechanisms. Front Oncol 5:39. https://doi.org/10.3389/fonc.2015.00039 CrossRefPubMedPubMedCentral

12.

Radons J (2016) The human HSP70 family of chaperones: Where do we stand? Cell Stress Chaperones 21(3):379–404. https://doi.org/10.1007/s12192-016-0676-6 CrossRefPubMedPubMedCentral

13.

Finka A, Sood V, Quadroni M, Rios Pde L, Goloubinoff P (2015) Quantitative proteomics of heat-treated human cells show an across-the-board mild depletion of housekeeping proteins to massively accumulate few HSPs. Cell Stress Chaperones 20(4):605–620. https://doi.org/10.1007/s12192-015-0583-2 CrossRefPubMedPubMedCentral

14.

Multhoff G, Hightower LE (2011) Distinguishing integral and receptor-bound heat shock protein 70 (Hsp70) on the cell surface by Hsp70-specific antibodies. Cell Stress Chaperones 16(3):251–255. https://doi.org/10.1007/s12192-010-0247-1 CrossRefPubMed

15.

Polla BS (1988) A role for heat shock proteins in inflammation? Immunol Today 9(5):134–137. https://doi.org/10.1016/0167-5699(88)91199-1 CrossRefPubMed

16.

Efthymiou CA, Mocanu MM, de Belleroche J, Wells DJ, Latchmann DS, Yellon DM (2004) Heat shock protein 27 protects the heart against myocardial infarction. Basic Res Cardiol 99(6):392–394. https://doi.org/10.1007/s00395-004-0483-6 CrossRefPubMed

17.

Nishizawa J, Nakai A, Higashi T, Tanabe M, Nomoto S, Matsuda K, Ban T, Nagata K (1996) Reperfusion causes significant activation of heat shock transcription factor 1 in ischemic rat heart. Circulation 94(9):2185–2192CrossRefPubMed

18.

Kee HJ, Eom GH, Joung H, Shin S, Kim JR, Cho YK, Choe N, Sim BW, Jo D, Jeong MH, Kim KK, Seo JS, Kook H (2008) Activation of histone deacetylase 2 by inducible heat shock protein 70 in cardiac hypertrophy. Circ Res 103(11):1259–1269. https://doi.org/10.1161/01.res.0000338570.27156.84 CrossRefPubMed

19.

Henninger C, Huelsenbeck S, Wenzel P, Brand M, Huelsenbeck J, Schad A, Fritz G (2015) Chronic heart damage following doxorubicin treatment is alleviated by lovastatin. Pharmacol Res 91:47–56. https://doi.org/10.1016/j.phrs.2014.11.003 CrossRefPubMed

20.

Dehbi M, Baturcam E, Eldali A, Ahmed M, Kwaasi A, Chishti MA, Bouchama A (2010) Hsp-72, a candidate prognostic indicator of heatstroke. Cell Stress Chaperones 15(5):593–603. https://doi.org/10.1007/s12192-010-0172-3 CrossRefPubMedPubMedCentral

21.

Zhao Y, Wang W, Qian L (2007) Hsp70 may protect cardiomyocytes from stress-induced injury by inhibiting Fas-mediated apoptosis. Cell Stress Chaperones 12(1):83–95CrossRefPubMedPubMedCentral

22.

Patties I, Haagen J, Dorr W, Hildebrandt G, Glasow A (2015) Late inflammatory and thrombotic changes in irradiated hearts of C57BL/6 wild-type and atherosclerosis-prone ApoE-deficient mice. Strahlenther Onkol 191(2):172–179. https://doi.org/10.1007/s00066-014-0745-7 CrossRefPubMed

23.

Monceau V, Meziani L, Strup-Perrot C, Morel E, Schmidt M, Haagen J, Escoubet B, Dorr W, Vozenin MC (2013) Enhanced sensitivity to low dose irradiation of ApoE−/− mice mediated by early pro-inflammatory profile and delayed activation of the TGFbeta1 cascade involved in fibrogenesis. PLOS ONE 8(2):e57052. https://doi.org/10.1371/journal.pone.0057052 CrossRefPubMedPubMedCentral

24.

Gomori G (1950) A rapid one-step trichrome stain. Am J Clin Pathol 20(7):661–664CrossRefPubMed

25.

Shapiro SS, Wilk MB (1965) An analysis of variance test for normality (complete samples). Biometrika 52(3–4):591–611. https://doi.org/10.1093/biomet/52.3-4.591 CrossRef

26.

Brown MB, Forsythe AB (1974) Robust tests for equality of variances. J Am Stat Assoc 69:364–367CrossRef

27.

Mann HB, Whitney DR (1947) On a test of whether one of two random variables is stochastically larger than the other. Ann Math Stat 18(1):50–60CrossRef

28.

Hodges JL, Lehmann E (2005) Basic concepts of probability and statistics. Classics in applied mathematics. SIAM, Philadelphia. https://doi.org/10.1137/1.9780898719123 CrossRef

29.

Violet JA, Harmer C (2004) Breast cancer: improving outcome following adjuvant radiotherapy. Br J Radiol 77(922):811–820. https://doi.org/10.1259/bjr/44576710 CrossRefPubMed

30.

Aleman BM, van den Belt-Dusebout AW, Klokman WJ, Van’t Veer MB, Bartelink H, van Leeuwen FE (2003) Long-term cause-specific mortality of patients treated for Hodgkin’s disease. J Clin Oncol 21(18):3431–3439. https://doi.org/10.1200/jco.2003.07.131 CrossRefPubMed

31.

Jelonek K, Walaszczyk A, Gabrys D, Pietrowska M, Kanthou C, Widlak P (2011) Cardiac endothelial cells isolated from mouse heart – a novel model for radiobiology. Acta Biochim Pol 58(3):397–404PubMed

32.

Gabriels K, Hoving S, Seemann I, Visser NL, Gijbels MJ, Pol JF, Daemen MJ, Stewart FA, Heeneman S (2012) Local heart irradiation of ApoE(−/−) mice induces microvascular and endocardial damage and accelerates coronary atherosclerosis. Radiother Oncol 105(3):358–364. https://doi.org/10.1016/j.radonc.2012.08.002 CrossRefPubMed

33.

Seemann I, Gabriels K, Visser NL, Hoving S, te Poele JA, Pol JF, Gijbels MJ, Janssen BJ, van Leeuwen FW, Daemen MJ, Heeneman S, Stewart FA (2012) Irradiation induced modest changes in murine cardiac function despite progressive structural damage to the myocardium and microvasculature. Radiother Oncol 103(2):143–150. https://doi.org/10.1016/j.radonc.2011.10.011 CrossRefPubMed

34.

Azimzadeh O, Sievert W, Sarioglu H, Merl-Pham J, Yentrapalli R, Bakshi MV, Janik D, Ueffing M, Atkinson MJ, Multhoff G, Tapio S (2015) Integrative Proteomics and targeted transcriptomics analyses in cardiac Endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction. J Proteome Res 14(2):1203–1219. https://doi.org/10.1021/pr501141b CrossRefPubMed

35.

Stewart FA (2012) Mechanisms and dose-response relationships for radiation-induced cardiovascular disease. Ann ICRP 41(3–4):72–79. https://doi.org/10.1016/j.icrp.2012.06.031 CrossRefPubMed

36.

Kania G, Blyszczuk P, Eriksson U (2009) Mechanisms of cardiac fibrosis in inflammatory heart disease. Trends Cardiovasc Med 19(8):247–252. https://doi.org/10.1016/j.tcm.2010.02.005 CrossRefPubMed

37.

Stewart FA, Hoving S, Russell NS (2010) Vascular damage as an underlying mechanism of cardiac and cerebral toxicity in irradiated cancer patients. Radiat Res 174(6):865–869. https://doi.org/10.1667/rr1862.1 CrossRefPubMed

38.

Strait JB, Lakatta EG (2012) Aging-associated cardiovascular changes and their relationship to heart failure. Heart Fail Clin 8(1):143–164. https://doi.org/10.1016/j.hfc.2011.08.011 CrossRefPubMedPubMedCentral

39.

Calini V, Urani C, Camatini M (2003) Overexpression of HSP70 is induced by ionizing radiation in C3H 10T1/2 cells and protects from DNA damage. Toxicol In Vitro 17(5):561–566CrossRefPubMed

40.

Li Z, Song Y, Xing R, Yu H, Zhang Y, Li Z, Gao W (2013) Heat shock protein 70 acts as a potential biomarker for early diagnosis of heart failure. PLOS ONE 8(7):e67964. https://doi.org/10.1371/journal.pone.0067964 CrossRefPubMedPubMedCentral

41.

Trost SU, Omens JH, Karlon WJ, Meyer M, Mestril R, Covell JW, Dillmann WH (1998) Protection against myocardial dysfunction after a brief ischemic period in transgenic mice expressing inducible heat shock protein 70. J Clin Invest 101(4):855–862. https://doi.org/10.1172/jci265 CrossRefPubMedPubMedCentral

42.

Martinez de Toda I, De la Fuente M (2015) The role of Hsp70 in oxi-inflamm-aging and its use as a potential biomarker of lifespan. Biogerontology 16(6):709–721. https://doi.org/10.1007/s10522-015-9607-7 CrossRefPubMed

43.

Njemini R, Bautmans I, Onyema OO, Van Puyvelde K, Demanet C, Mets T (2011) Circulating heat shock protein 70 in health, aging and disease. Bmc Immunol 12:24. https://doi.org/10.1186/1471-2172-12-24 CrossRefPubMedPubMedCentral

44.

de Toda IM, Vida C, Ortega E, De La Fuente M (2016) Hsp70 basal levels, a tissue marker of the rate of aging and longevity in mice. Exp Gerontol 84:21–28. https://doi.org/10.1016/j.exger.2016.08.013 CrossRefPubMed

45.

Nikodemova M, Watters JJ (2011) Outbred ICR/CD1 mice display more severe neuroinflammation mediated by microglial TLR4/CD14 activation than inbred C57Bl/6 mice. Neuroscience 190:67–74. https://doi.org/10.1016/j.neuroscience.2011.06.006 CrossRefPubMedPubMedCentral

46.

Voss MR, Stallone JN, Li M, Cornelussen RN, Knuefermann P, Knowlton AA (2003) Gender differences in the expression of heat shock proteins: The effect of estrogen. Am J Physiol Heart Circ Physiol 285(2):H687–H692. https://doi.org/10.1152/ajpheart.01000.2002 CrossRefPubMed

47.

de Jong PR, Schadenberg AW, Jansen NJ, Prakken BJ (2009) Hsp70 and cardiac surgery: Molecular chaperone and inflammatory regulator with compartmentalized effects. Cell Stress Chaperones 14(2):117–131. https://doi.org/10.1007/s12192-008-0066-9 CrossRefPubMed

48.

Bernardo BC, Weeks KL, Patterson NL, McMullen JR (2016) HSP70: Therapeutic potential in acute and chronic cardiac disease settings. Future Med Chem 8(18):2177–2183. https://doi.org/10.4155/fmc-2016-0192 CrossRefPubMed

Title: Heart irradiation reduces microvascular density and accumulation of HSPA1 in mice
Authors: Anna Walaszczyk
Katarzyna Szołtysek
Karol Jelonek
Joanna Polańska
Wolfgang Dörr
Julia Haagen
Piotr Widłak
Dorota Gabryś, PhD, MD
Publication date: 01-03-2018
Publisher: Springer Berlin Heidelberg
Published in: Strahlentherapie und Onkologie / Issue 3/2018
Print ISSN: 0179-7158
Electronic ISSN: 1439-099X
DOI: https://doi.org/10.1007/s00066-017-1220-z

At a glance: The STEP trials

Springer Medicine

Heart irradiation reduces microvascular density and accumulation of HSPA1 in mice

Abstract

Purpose

Materials and methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Materials and methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2018

Concurrent radiotherapy with temozolomide vs. concurrent radiotherapy with a cisplatinum-based polychemotherapy regimen

Real-time beam monitoring for error detection in IMRT plans and impact on dose-volume histograms

Durvalumab verbessert die Prognose beim lokal fortgeschrittenen nicht-kleinzelligen Bronchialkarzinom nach definitiver Radiochemotherapie

Medulloblastoma in adults

Nachruf für Prof. Dr. med. Dr. hc. Wilhelm Oelßner, langjähriges Ehrenmitglied der DEGRO

Reirradiation + hyperthermia for recurrent breast cancer en cuirasse