MiR-21 Protected Cardiomyocytes Against Doxorubicin-Induced Apoptosis by Targeting BTG2

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2015 Jul 2

PMID 26132560

Citations 43

Authors

Zhongyi Tong

Bimei Jiang

Yanyang Wu

Yanjuan Liu

Yuanbin Li

Min Gao

Yu Jiang

Qinglan Lv

Xianzhong Xiao

Affiliations

Soon will be listed here.

Abstract

Doxorubicin (DOX) is an anthracycline drug with a wide spectrum of antineoplastic activities. However, it causes cardiac cytotoxicity, and this limits its clinical applications. MicroRNA-21 (miR-21) plays a vital role in regulating cell proliferation and apoptosis. While miR-21 is preferentially expressed in adult cardiomyocytes and involved in cardiac development and heart disease, little is known regarding its biological functions in responding to DOX-induced cardiac cytotoxicity. In this study, the effects of DOX on mouse cardiac function and the expression of miR-21 were examined in both mouse heart tissues and rat H9C2 cardiomyocytes. The results showed that the cardiac functions were more aggravated in chronic DOX injury mice compared with acute DOX-injury mice; DOX treatment significantly increased miR-21 expression in both mouse heart tissue and H9C2 cells. Over-expression of miR-21 attenuated DOX-induced apoptosis in cardiamyocytes whereas knocking down its expression increased DOX-induced apoptosis. These gain- and loss- of function experiments showed that B cell translocation gene 2 (BTG2) was a target of miR-21. The expression of BTG2 was significantly decreased both in myocardium and H9C2 cells treated with DOX. The present study has revealed that miR-21 protects mouse myocardium and H9C2 cells against DOX-induced cardiotoxicity probably by targeting BTG2.

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References

Tirone F . The gene PC3(TIS21/BTG2), prototype member of the PC3/BTG/TOB family: regulator in control of cell growth, differentiation, and DNA repair?. J Cell Physiol. 2001; 187(2):155-65. DOI: 10.1002/jcp.1062. View

Safra T, Muggia F, Jeffers S, Tsao-Wei D, Groshen S, Lyass O . Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol. 2000; 11(8):1029-33. DOI: 10.1023/a:1008365716693. View

Ambros V . The functions of animal microRNAs. Nature. 2004; 431(7006):350-5. DOI: 10.1038/nature02871. View

Lefrak E, Pitha J, ROSENHEIM S, Gottlieb J . A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973; 32(2):302-14. DOI: 10.1002/1097-0142(197308)32:2<302::aid-cncr2820320205>3.0.co;2-2. View

Buja L, Ferrans V, Mayer R, Roberts W, HENDERSON E . Cardiac ultrastructural changes induced by daunorubicin therapy. Cancer. 1973; 32(4):771-88. DOI: 10.1002/1097-0142(197310)32:4<771::aid-cncr2820320407>3.0.co;2-a. View

Feng Z, Tang Z, Li K, Liu B, Yu M, Zhao S . Molecular characterization of the BTG2 and BTG3 genes in fetal muscle development of pigs. Gene. 2007; 403(1-2):170-7. DOI: 10.1016/j.gene.2007.08.009. View

Thum T, Catalucci D, Bauersachs J . MicroRNAs: novel regulators in cardiac development and disease. Cardiovasc Res. 2008; 79(4):562-70. DOI: 10.1093/cvr/cvn137. View

Fan G, Zhou X, Wang X, Song G, Qian J, Nicolaou P . Heat shock protein 20 interacting with phosphorylated Akt reduces doxorubicin-triggered oxidative stress and cardiotoxicity. Circ Res. 2008; 103(11):1270-9. PMC: 2763388. DOI: 10.1161/CIRCRESAHA.108.182832. View

Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M . MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008; 456(7224):980-4. DOI: 10.1038/nature07511. View

10.

Roy S, Khanna S, Hussain S, Biswas S, Azad A, Rink C . MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue. Cardiovasc Res. 2009; 82(1):21-9. PMC: 2652741. DOI: 10.1093/cvr/cvp015. View

11.

Liu M, Wu H, Liu T, Li Y, Wang F, Wan H . Regulation of the cell cycle gene, BTG2, by miR-21 in human laryngeal carcinoma. Cell Res. 2009; 19(7):828-37. DOI: 10.1038/cr.2009.72. View

12.

Nakamura T, Ueda Y, Juan Y, Katsuda S, Takahashi H, Koh E . Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats: In vivo study. Circulation. 2000; 102(5):572-8. DOI: 10.1161/01.cir.102.5.572. View

13.

Zhang S, Han L, Wei J, Shi Z, Pu P, Zhang J . Combination treatment with doxorubicin and microRNA-21 inhibitor synergistically augments anticancer activity through upregulation of tumor suppressing genes. Int J Oncol. 2015; 46(4):1589-600. DOI: 10.3892/ijo.2015.2841. View

14.

Dong S, Cheng Y, Yang J, Li J, Liu X, Wang X . MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction. J Biol Chem. 2009; 284(43):29514-25. PMC: 2785585. DOI: 10.1074/jbc.M109.027896. View

15.

Zhang Y, Shi J, Li Y, Wei L . Cardiomyocyte death in doxorubicin-induced cardiotoxicity. Arch Immunol Ther Exp (Warsz). 2009; 57(6):435-45. PMC: 2809808. DOI: 10.1007/s00005-009-0051-8. View

16.

Jazbutyte V, Thum T . MicroRNA-21: from cancer to cardiovascular disease. Curr Drug Targets. 2010; 11(8):926-35. DOI: 10.2174/138945010791591403. View

17.

Zhang C, Feng Y, Qu S, Wei X, Zhu H, Luo Q . Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53. Cardiovasc Res. 2011; 90(3):538-45. DOI: 10.1093/cvr/cvr022. View

18.

Zhao L, Chen X, Cao Y . New role of microRNA: carcinogenesis and clinical application in cancer. Acta Biochim Biophys Sin (Shanghai). 2011; 43(11):831-9. DOI: 10.1093/abbs/gmr080. View

19.

Krishnamurthy K, Kanagasabai R, Druhan L, Ilangovan G . Heat shock protein 25-enriched plasma transfusion preconditions the heart against doxorubicin-induced dilated cardiomyopathy in mice. J Pharmacol Exp Ther. 2012; 341(3):829-39. PMC: 3362880. DOI: 10.1124/jpet.112.192245. View

20.

Wei S, Hao C, Li X, Zhao H, Chen J, Zhou Q . Effects of BTG2 on proliferation inhibition and anti-invasion in human lung cancer cells. Tumour Biol. 2012; 33(4):1223-30. DOI: 10.1007/s13277-012-0370-y. View