title: miR-320a mediates doxorubicin-induced cardiotoxicity by targeting VEGF signal pathway.
abstract: BACKGROUND
  Vascular homeostasis abnormalities may involve in doxorubicin induced cardiotoxicity.
  
  
  METHODS
  Enhanced cardiac miR-320a expression, reduced cardiac microvessel density and impaired cardiac function were observed in mice treated by anthracycline doxorubicin. To further explore the role of miR-320a in doxorubicin induced cardiotoxicity, microRNA mimics/inhibitor in vitro and rAAV administration in vivo were employed in mice.
  
  
  RESULTS
  Knockdown of miR-320a not only resulted in enhanced proliferation and inhibited apoptosis in cultured endothelial cells, but also attenuated cardiac abnormalities induced by doxorubicin. On the contrary, overexpression of miR-320a enhanced apoptosis in vitro, and aggravated vessel abnormalities in heart and subsequent cardiac dysfunction in mice. Furthermore, Western blot assays showed that VEGF-A was a potential target of miR-320a, which was verified by anti-Ago2 co-immunoprecipitation. Moreover, as same as miR-320a, siRNA against VEGF-A reinforced doxorubicin induced endothelial cells injury. Finally, the negative effects of miR-320a on vascular homeostasis and cardiac function were alleviated by VEGF-A re-expression in doxorubicin treated mice.
  
  
  CONCLUSIONS
  Our observations demonstrate that miR-320a play important roles in doxorubicin induced cardiotoxicity via vessel homeostasis in heart and thus, inhibition of miR-320a may be applied to the treatment of cardiac dysfunction induced by anthracycline.
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Yanru
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Huaping
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Mengwen
authors.initials: M
authors.lastname: Yan
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Departments of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D066126:Cardiotoxicity; D002460:Cell Line; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004317:Doxorubicin; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006331:Heart Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C541056:Mirn320 microRNA, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D004317:Doxorubicin
keywords: VEGF-A; cardiotoxicity; doxorubicin; miR-320a; vascular homeostasis
references.citation: J Pharmacol Exp Ther. 2003 Nov;307(2):753-64
references.pmid: 12975498
references.citation: Nat Med. 2012 Nov;18(11):1639-42
references.pmid: 23104132
references.citation: Curr Med Chem. 2009;16(25):3267-85
references.pmid: 19548866
references.citation: Cancer Manag Res. 2015 Jun 03;7:133-43
references.pmid: 26082660
references.citation: Ann Intern Med. 1979 Nov;91(5):710-7
references.pmid: 496103
references.citation: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5780-5
references.pmid: 11331753
references.citation: Hypertension. 2003 Feb;41(2):249-54
references.pmid: 12574090
references.citation: J Biol Chem. 2012 Apr 6;287(15):12309-20
references.pmid: 22294688
references.citation: J Clin Oncol. 2005 Oct 1;23(28):7135-42
references.pmid: 16192597
references.citation: J Mol Cell Cardiol. 2002 Dec;34(12):1595-607
references.pmid: 12505058
references.citation: Vascul Pharmacol. 2011 Mar-Jun;54(3-6):59-67
references.pmid: 21440088
references.citation: Mayo Clin Proc. 2014 Sep;89(9):1287-306
references.pmid: 25192616
references.citation: PLoS One. 2012;7(2):e31393
references.pmid: 22384017
references.citation: Nat Methods. 2012 Apr;9(4):403-9
references.pmid: 22388288
references.citation: J Mol Cell Cardiol. 2012 Jun;52(6):1213-25
references.pmid: 22465037
references.citation: Med Res Rev. 2014 Jan;34(1):106-35
references.pmid: 23494977
references.citation: J Biol Chem. 2012 Oct 12;287(42):34866-82
references.pmid: 22908232
references.citation: J Am Coll Cardiol. 2014 Sep 2;64(9):938-45
references.pmid: 25169180
references.citation: Cell Death Dis. 2015;6:e1677
references.pmid: 25766316
references.citation: Microcirculation. 2014 May;21(4):315-23
references.pmid: 24521511
references.citation: Circulation. 2015 Jun 2;131(22):1981-8
references.pmid: 25948538
references.citation: Cardiovasc Res. 1993 Jul;27(7):1368-73
references.pmid: 8252601
references.citation: Science. 2007 Apr 27;316(5824):575-9
references.pmid: 17379774
references.citation: Circulation. 1999 Sep 21;100(12):1338-45
references.pmid: 10491380
references.citation: RNA. 2010 Feb;16(2):394-404
references.pmid: 20042474
references.citation: J Clin Invest. 2014 Sep;124(9):4039-51
references.pmid: 25105365
references.citation: Circ Res. 1998 Sep 7;83(5):516-22
references.pmid: 9734474
references.citation: Nat Rev Cardiol. 2013 Sep;10(9):519-30
references.pmid: 23856679
references.citation: Circulation. 2009 Mar 10;119(9):1241-52
references.pmid: 19237664
references.citation: J Ultrasound Med. 2010 Dec;29(12):1771-8
references.pmid: 21098849
references.citation: Circulation. 2002 Jan 15;105(2):186-93
references.pmid: 11790699
references.citation: Nat Rev Genet. 2012 Apr;13(4):271-82
references.pmid: 22411466
references.citation: J Cell Mol Med. 2015 May;19(5):970-85
references.pmid: 25728840
references.citation: Eur J Heart Fail. 2007 Oct;9(10):995-1002
references.pmid: 17719840
references.citation: Circ Res. 1995 Sep;77(3):486-93
references.pmid: 7543825
references.citation: J Am Coll Cardiol. 2009 Jun 16;53(24):2231-47
references.pmid: 19520246