title: Downregulation of miR-151-5p contributes to increased susceptibility to arrhythmogenesis during myocardial infarction with estrogen deprivation.
abstract: Estrogen deficiency is associated with increased incidence of cardiovascular diseases. But merely estrogen supplementary treatment can induce many severe complications such as breast cancer. The present study was designed to elucidate molecular mechanisms underlying increased susceptibility of arrhythmogenesis during myocardial infarction with estrogen deprivation, which provides us a new target to cure cardiac disease accompanied with estrogen deprivation. We successfully established a rat model of myocardial ischemia (MI) accompanied with estrogen deprivation by coronary artery ligation and ovariectomy (OVX). Vulnerability and mortality of ventricular arrhythmias increased in estrogen deficiency rats compared to non estrogen deficiency rats when suffered MI, which was associated with down-regulation of microRNA-151-5p (miR-151-5p). Luciferase Reporter Assay demonstrated that miR-151-5p can bind to the 3'-UTR of FXYD1 (coding gene of phospholemman, PLM) and inhibit its expression. We found that the expression of PLM was increased in (OVX+MI) group compared with MI group. More changes such as down-regulation of Kir2.1/IK1, calcium overload had emerged in (OVX+MI) group compared to MI group merely. Transfection of miR-151-5p into primary cultured myocytes decreased PLM levels and [Ca(2+)]i, however, increased Kir2.1 levels. These effects were abolished by the antisense oligonucleotides against miR-151-5p. Co-immunoprecipitation and immunofluorescent experiments confirmed the co-localization between Kir2.1 and PLM in rat ventricular tissue. We conclude that the increased ventricular arrhythmias vulnerability in response to acute myocardial ischemia in rat is critically dependent upon down-regulation of miR-151-5p. These findings support the proposal that miR-151-5p could be a potential therapeutic target for the prevention of ischemic arrhythmias in the subjects with estrogen deficiency.
authors.affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Renjun
authors.initials: R
authors.lastname: Wang
authors.forename: Weijie
authors.initials: W
authors.lastname: Du
authors.forename: Shuxuan
authors.initials: S
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Pan
authors.forename: Xuelian
authors.initials: X
authors.lastname: Li
authors.forename: Xuehui
authors.initials: X
authors.lastname: Xiong
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.forename: Yongfang
authors.initials: Y
authors.lastname: Shi
authors.forename: Xue
authors.initials: X
authors.lastname: Liu
authors.forename: Shaonan
authors.initials: S
authors.lastname: Yu
authors.forename: Zhengang
authors.initials: Z
authors.lastname: Bi
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.forename: Hongli
authors.initials: H
authors.lastname: Shan
mesh_terms: D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000401:mortality / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D004967:Estrogens / Q000172:deficiency / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009203:Myocardial Infarction / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D017202:Myocardial Ischemia / Q000150:complications / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats
chemical_list: D004967:Estrogens; C489461:Kir2.1 channel; C000588814:MIRN151 microRNA, rat; D035683:MicroRNAs; D024661:Potassium Channels, Inwardly Rectifying; D002118:Calcium
references.citation: Environ Health Perspect. 2010 Nov;118(11):1597-602
references.pmid: 20562052
references.citation: J Biol Chem. 1985 Nov 5;260(25):13879-89
references.pmid: 2997184
references.citation: Biochem Biophys Res Commun. 2006 Feb 24;340(4):1192-9
references.pmid: 16406237
references.citation: Nat Cell Biol. 2010 Apr;12(4):390-9
references.pmid: 20305651
references.citation: Cardiovasc Res. 2002 Feb 15;53(3):605-19
references.pmid: 11861031
references.citation: Hypertension. 2010 Apr;55(4):946-52
references.pmid: 20177001
references.citation: Am J Physiol Heart Circ Physiol. 2004 Apr;286(4):H1322-30
references.pmid: 14684371
references.citation: J Biol Chem. 2005 May 20;280(20):19875-82
references.pmid: 15774479
references.citation: J Appl Physiol (1985). 2006 Jan;100(1):212-20
references.pmid: 16195392
references.citation: Nat Med. 2007 Apr;13(4):486-91
references.pmid: 17401374
references.citation: Physiol Genomics. 2007 Nov 14;31(3):367-73
references.pmid: 17712037
references.citation: FEBS Lett. 2008 Dec 24;582(30):4137-42
references.pmid: 19041309
references.citation: J Cell Physiol. 2007 Aug;212(2):358-67
references.pmid: 17443681
references.citation: Zhongguo Yao Li Xue Bao. 1998 May;19(3):269-72
references.pmid: 10375742
references.citation: J Biol Chem. 1986 Apr 15;261(11):4860-7
references.pmid: 2420794
references.citation: Cardiovasc Res. 1988 Sep;22(9):656-65
references.pmid: 3242835
references.citation: Sci STKE. 2007 Jan 02;2007(367):re1
references.pmid: 17200520
references.citation: Circulation. 1993 Oct;88(4 Pt 1):1999-2009
references.pmid: 8403349
references.citation: Circ Res. 2005 Aug 5;97(3):252-9
references.pmid: 16002746
references.citation: Nat Rev Genet. 2011 Nov 18;12(12):861-74
references.pmid: 22094949
references.citation: Curr Opin Pharmacol. 2009 Apr;9(2):160-6
references.pmid: 19195931
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11476-81
references.pmid: 12169672
references.citation: Br J Pharmacol. 2009 Nov;158(5):1227-35
references.pmid: 19775284
references.citation: J Biol Chem. 2009 Oct 23;284(43):29514-25
references.pmid: 19706597
references.citation: Nucleic Acids Res. 2010 Jul;38(13):4476-86
references.pmid: 20299343
references.citation: Cancer Res. 2002 Sep 1;62(17):4843-8
references.pmid: 12208728
references.citation: Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H576-83
references.pmid: 12124204
references.citation: Cell Physiol Biochem. 2005;16(4-6):163-74
references.pmid: 16301817
references.citation: Ann Intern Med. 1992 Dec 15;117(12):1016-37
references.pmid: 1443971
references.citation: Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):104-9
references.pmid: 16433899
references.citation: Acta Pharmacol Sin. 2004 Jun;25(6):751-5
references.pmid: 15169627
references.citation: Biophys J. 2010 Apr 7;98(7):1149-59
references.pmid: 20371314
references.citation: Prev Med. 1991 Jan;20(1):47-63
references.pmid: 1826173
references.citation: Biol Pharm Bull. 2009 Sep;32(9):1521-6
references.pmid: 19721226
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13027-32
references.pmid: 18723672
references.citation: Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2342-54
references.pmid: 15653756
references.citation: Am Heart J. 1986 Feb;111(2):383-90
references.pmid: 3946178
references.citation: Circulation. 2000 Apr 25;101(16):1990-9
references.pmid: 10779467
references.citation: J Biol Chem. 1985 Mar 25;260(6):3860-7
references.pmid: 2982878
references.citation: Nature. 2005 Mar 17;434(7031):338-45
references.pmid: 15735639
references.citation: FEBS Lett. 2003 Jul 10;546(2-3):349-54
references.pmid: 12832067
references.citation: Am J Physiol Heart Circ Physiol. 2003 Jan;284(1):H225-33
references.pmid: 12388273
references.citation: J Biol Chem. 2009 Sep 25;284(39):26749-57
references.pmid: 19638348
references.citation: Ann Intern Med. 1997 Oct 1;127(7):501-8
references.pmid: 9313017