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CLC number: R542.2

On-line Access: 2016-12-05

Received: 2016-06-08

Revision Accepted: 2016-08-19

Crosschecked: 2016-11-10

Cited: 0

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Citations:  Bibtex RefMan EndNote GB/T7714


Li-juan Shen


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Journal of Zhejiang University SCIENCE B 2016 Vol.17 No.12 P.975-983


Developing a rat model of dilated cardiomyopathy with improved survival

Author(s):  Li-juan Shen, Shu Lu, Yong-hua Zhou, Lan Li, Qing-min Xing, Yong-liang Xu

Affiliation(s):  Wuxi Hospital of Traditional Chinese Medicine, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi 214071, China; more

Corresponding email(s):   Panda55007@163.com, toxo2001@163.com

Key Words:  Doxorubicin, Dilated cardiomyopathy, Animal model, 18FDG-PET

Li-juan Shen, Shu Lu, Yong-hua Zhou, Lan Li, Qing-min Xing, Yong-liang Xu. Developing a rat model of dilated cardiomyopathy with improved survival[J]. Journal of Zhejiang University Science B, 2016, 17(12): 975-983.

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journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

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%T Developing a rat model of dilated cardiomyopathy with improved survival
%A Li-juan Shen
%A Shu Lu
%A Yong-hua Zhou
%A Lan Li
%A Qing-min Xing
%A Yong-liang Xu
%J Journal of Zhejiang University SCIENCE B
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%D 2016
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1600257

T1 - Developing a rat model of dilated cardiomyopathy with improved survival
A1 - Li-juan Shen
A1 - Shu Lu
A1 - Yong-hua Zhou
A1 - Lan Li
A1 - Qing-min Xing
A1 - Yong-liang Xu
J0 - Journal of Zhejiang University Science B
VL - 17
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%@ 1673-1581
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PB - Zhejiang University Press & Springer
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DOI - 10.1631/jzus.B1600257

To compare the continuous infusion and intermittent bolus injection administration protocols of doxorubicin (Dox) under the same cumulative dose (12 mg/kg), and establish a rat dilated cardiomyopathy model with improved survival, a total of 150 Sprague-Dawley (SD) rats were divided into three groups: a control group, administered with normal saline; a Dox 1 group, administration twice a week at 1 mg/kg; a Dox 2, administration once a week at 2 mg/kg. Mortality rates in the Dox 1 and Dox 2 groups were 22% and 48%, respectively (P<0.05). As shown by echocardiography, both Dox groups exhibited significant chamber dilatation and reduced cardiac function (all P<0.05 vs. control). Plasma brain natriuretic peptide and C-reactive protein concentrations were significantly increased (P<0.05) with both Dox regimens. The concentrations of Caspase-3 in myocardial tissues of rats significantly increased in both doxorubicin regimens. Myocardial metabolism imaging by histology and 18F-fluoro-deoxyglucose-positron emission tomography (18FDG-PET) both revealed decreased myocardial viability and necrosis, and even interstitial fibrosis, in left ventricles (LVs) in both Dox groups. Serum creatinine and aspartate aminotransferase concentrations were significantly higher in the Dox 2 model than in the Dox 1 model. doxorubicin given at both regimens induced dilated cardiomyopathy, while its administration at lower doses with more frequent infusions reduced the mortality rate.


目的:比较在腹腔注射相同剂量阿霉素(12 mg/kg)下,不同给药方案构建扩张型心肌病大鼠模型的生存率。
创新点:首次应用腹腔注射阿霉素1 mg/kg,一周两次的方法构建扩张型心肌病大鼠模型,并与常规的方法进行生存率的比较。
方法:将150只SD雄鼠分为对照组(腹腔注射生理盐水)、Dox 1组(腹腔注射阿霉素1 mg/kg一周两次,共六周)和Dox 2组(腹腔注射阿霉素2 mg/kg一周一次,共六周)。观察及比较各组大鼠的体重、生存率、心腔大小、pro-BNP、CRP、CREA、AST和Caspase-3 mRNA水平。观察各组大鼠心肌病理变化,同时进行18FDG-PET心肌代谢显像。
结论:本实验中结果显示,Dox 1组和Dox 2组在pro-BNP、Caspase-3 mRNA水平、心肌病理变化及18FDG-PET心肌代谢显像上均没有明显差异;但Dox 1组的生存率是78%,而Dox 2组的生存率是52%;同时,Dox 2组大鼠的血清CREA、AST和CRP水平比Dox 1组明显升高。综上所述,腹腔注射阿霉素1 mg/kg一周两次的方法在成功构建扩张型心肌病大鼠模型的同时大大提高了存活率。


Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Baba, S., Heike, T., Yoshimoto, M., et al., 2007. Flk1+ cardiac stem/progenitor cells derived from embryonic stem cells improve cardiac function in a dilated cardiomyopathy mouse model. Cardiovasc. Res., 76(1):119-131.

[2]Bardi, E., Bobok, I., Olah, A.V., et al., 2007. Anthracycline antibiotics induce acute renal tubular toxicity in children with cancer. Pathol. Oncol. Res., 13(3):249-253.

[3]Brunner, S., Todica, A., Boning, G., et al., 2012. Left ventricular functional assessment in murine models of ischemic and dilated cardiomyopathy using [18F]FDG-PET: comparison with cardiac MRI and monitoring erythropoietin therapy. EJNMMI Res., 2(1):43.

[4]Carvalho, C., Santos, R.X., Cardoso, S., et al., 2009. Doxorubicin: the good, the bad and the ugly effect. Curr. Med. Chem., 16(25):3267-3285.

[5]Cryns, V., Yuan, J., 1998. Proteases to die for. Genes Dev., 12(11):1551-1570.

[6]Delgado-Roche, L., Hernandez-Matos, Y., Medina, E.A., et al., 2014. Ozone-oxidative preconditioning prevents doxorubicin-induced cardiotoxicity in Sprague-Dawley Rats. Sultan Qaboos Univ. Med. J., 14(3):e342-e348.

[7]Deng, S., Kruger, A., Schmidt, A., et al., 2009. Differential roles of nitric oxide synthase isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice. Naunyn-Schmiedeberg’s Arch. Pharmacol., 380(1):25-34.

[8]El-Sayyad, H.I., Ismail, M.F., Shalaby, F.M., et al., 2009. Histopathological effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats. Int. J. Biol. Sci., 5(5):466-473.

[9]Faleiro, L., Kobayashi, R., Fearnhead, H., et al., 1997. Multiple species of CPP32 and MCh2 are the major active Caspases present in apoptotic cells. EMBO, 16(9):2271-2281.

[10]Gava, F.N., Zacche, E., Ortiz, E.M., et al., 2013. Doxorubicin induced dilated cardiomyopathy in a rabbit model: an update. Res. Vet. Sci., 94(1):115-121.

[11]Gu, R., Bai, J., Ling, L., et al., 2012. Increased expression of integrin-linked kinase improves cardiac function and decreases mortality in dilated cardiomyopathy model of rats. PLoS ONE, 7(2):e31279.

[12]Haider, N., Narula, J., Hajjar, R.J., et al., 1995. Apoptosis in human explanted cardiomyopathic hearts suggests programmed progression of dilatedcardiomyopathy. Circulation, 92(8):3479-3479.

[13]Handa, N., Magata, Y., Mukai, T., et al., 2007. Quantitative FDG-uptake by positron emission tomography in progressive hypertrophy of rat hearts in vivo. Ann. Nucl. Med., 21(10):569-576.

[14]Hayward, R., Hydock, D.S., 2007. Doxorubicin cardiotoxicity in the rat: an in vivo characterization. J. Am. Assoc. Lab. Anim. Sci., 46(4):20-32.

[15]Ishida, M., Tomita, S., Nakatani, T., et al., 2004. Bone marrow mononuclear cell transplantation had beneficial effects on doxorubicin-induced cardiomyopathy. J. Heart Lung Transplant., 23(4):436-445.

[16]Iwata, Y., Ohtake, H., Suzuki, O., et al., 2013. Blockade of sarcolemmal TRPV2 accumulation inhibits progression of dilated cardiomyopathy. Cardiovasc. Res., 99(4):760-768.

[17]Jones, R.L., Swanton, C., Ewer, M.S., 2006. Anthracycline cardiotoxicity. Expert Opin. Drug Saf., 5(6):791-809.

[18]Kalender, Y., Yel, M., Kalender, S., 2005. Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats. The effects of vitamin E and catechin. Toxicology, 209(1):39-45.

[19]Kawano, H., Okada, R., Kawano, Y., et al., 1994. Apoptosis in acute and chronic myocarditis. Jpn. Heart, 35(6):745-750.

[20]Leontyev, S., Schlegel, F., Spath, C., et al., 2013. Transplantation of engineered heart tissue as a biological cardiac assist device for treatment of dilated cardiomyopathy. Eur. J. Heart Fail., 15(1):23-35.

[21]Liu, H.Z., Gao, C.Y., Wang, X.Q., et al., 2012. Angiotensin(1-7) attenuates left ventricular dysfunction and myocardial apoptosis on rat model of adriamycin-induced dilated cardiomyopathy. Chin. J. Cardiol., 40(3):219-224 (in Chinese).

[22]Lou, H., Danelisen, I., Singal, P.K., 2005. Involvement of mitogen-activated protein kinases in adriamycin-induced cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol., 288(4):H1925-H1930.

[23]Lu, L., Wu, W., Yan, J., et al., 2009. Adriamycin-induced autophagic cardiomyocyte death plays a pathogenic role in a rat model of heart failure. Int. J. Cardiol., 134(1):82-90.

[24]Mamamtavrishvili, N.D., Kvirkveliia, A.A., Abashidze, R.I., et al., 2008. Role of immune inflammatory activity in chronic heart failure progress. Georgian Med. News, 160/161:30-34.

[25]Martins, L.M., Kottke, T., Mesner, P.W., et al., 1997. Activation of multiple interleukin 1 β-bconverting enzyme homologues in cytosol and nuclei of HL-60 cells during etoposideinduced apoptosis. J. Biol. Chem., 272(11):7421-7430.

[26]Nicholson, D.W., Thornberry, A., 1997. Caspase: killer proteases. Trends Biochem. Sci., 22(8):299-306.

[27]Octavia, Y., Tocchetti, C.G., Gabrielson, K.L., et al., 2012. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J. Mol. Cell. Cardiol., 52(6):1213-1225.

[28]Plana, J.C., Galderisi, M., Barac, A., et al., 2014. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur. Heart J. Cardiovasc. Imaging, 15(10):1063-1093.

[29]Polverino, A.J., Patterson, S.D., 1997. Selective activation of caspases during apoptotic induction in HL-60 cells. J. Biol. Chem., 272(11):7013-7021.

[30]Satoh, M., Nakmura, M., Akatsu, T., et al., 2005. C-reactive protein co-expresses with tumor necrosis factor-α in the myocardium in human dilated cardiomyopathy. Eur. J. Heart Fail., 7(5):748-754.

[31]Stegger, L., Schafers, K.P., Flogel, U., et al., 2005. Monitoring left ventricular dilation in mice with PET. J. Nucl. Med., 46(9):1516-1521.

[32]Thornberry, N.A., Lazebnik, Y., 1998. Caspase: enemies within. Science, 281(5381):1312-1316.

[33]Turakhia, S., Venkatakrishnan, C.D., Dunsmore, K., et al., 2007. Doxorubicin-induced cardiotoxicity: direct correlation of cardiac fibroblast and H9c2 cell survival and aconitase activity with heat shock protein 27. Am. J. Physiol. Heart Circ. Physiol., 293(5):H3111-H3121.

[34]Vejpongsa, P., Yeh, E.T., 2014. Prevention of anthracycline-induced cardiotoxicity: challenges and opportunities. J. Am. Coll. Cardiol., 64(9):938-945.

[35]Yu, S.Y., Liu, L., Li, P., et al., 2013. Rapamycin inhibits the mTOR/p70S6K pathway and attenuates cardiac fibrosis in adriamycin-induced dilated cardiomyopathy. Thorac. Cardiovasc. Surg., 61(3):223-228.

[36]Zimmermann, O., Bienek-Ziolkowski, M., Wolf, B., et al., 2009. Myocardial inflammation and non-ischaemic heart failure: is there a role for C-reactive protein? Basic Res. Cardiol., 104(5):591-599.

[37]List of electronic supplementary materials

[38]Fig. S1 Myocardial metabolism imaging by 18FDG-PET/CT

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