title: MicroRNA in cardiovascular calcification: focus on targets and extracellular vesicle delivery mechanisms.
abstract: Cardiovascular calcification is a prominent feature of chronic inflammatory disorders-such as chronic kidney disease, type 2 diabetes mellitus, and atherosclerosis-that associate with significant morbidity and mortality. The concept that similar pathways control both bone remodeling and vascular calcification is widely accepted, but the precise mechanisms of calcification remain largely unknown. The central role of microRNAs (miRNA) as fine-tune regulators in the cardiovascular system and bone biology has gained acceptance and has raised the possibility for novel therapeutic targets. Additionally, circulating miRNAs have been proposed as biomarkers for a wide range of cardiovascular diseases, but knowledge of miRNA biology in cardiovascular calcification is very limited. This review focuses on the role of miRNAs in cardiovascular disease, with emphasis on osteogenic processes. Herein, we discuss the current understanding of miRNAs in cardiovascular calcification. Furthermore, we identify a set of miRNAs common to diseases associated with cardiovascular calcification (chronic kidney disease, type 2 diabetes mellitus, and atherosclerosis), and we hypothesize that these miRNAs may provide a molecular signature for calcification. Finally, we discuss this novel hypothesis with emphasis on known biological and pathological osteogenic processes (eg, osteogenic differentiation, release of calcifying matrix vesicles). The aim of this review is to provide an organized discussion of the known links between miRNA and calcification that provide emerging concepts for future studies on miRNA biology in cardiovascular calcification, which will be critical for developing new therapeutic strategies.
authors.affiliation: Harvard Medical School, Cardiovascular Medicine, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB-741, Boston, MA 02115, USA. eaikawa@partners.org
authors.forename: Claudia
authors.initials: C
authors.lastname: Goettsch
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hutcheson
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
mesh_terms: D000818:Animals; D002114:Calcinosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016503:Drug Delivery Systems; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*
chemical_list: D035683:MicroRNAs
references.citation: Eur J Clin Invest. 2009 May;39(5):359-67
references.pmid: 19371267
references.citation: Cell Tissue Res. 2010 Jan;339(1):189-95
references.pmid: 19649655
references.citation: Cardiovasc Res. 2012 Mar 15;93(4):633-44
references.pmid: 22258631
references.citation: FASEB J. 2007 Sep;21(11):2949-60
references.pmid: 17449718
references.citation: FEBS Lett. 2008 Apr 30;582(10):1552-7
references.pmid: 18405667
references.citation: Circ Res. 2001 Dec 7;89(12):1147-54
references.pmid: 11739279
references.citation: BMC Genomics. 2007 Jun 12;8:166
references.pmid: 17565689
references.citation: J Cell Biochem. 2007 Jul 1;101(4):996-9
references.pmid: 17471500
references.citation: Gene. 2012 Jan 15;492(1):1-18
references.pmid: 22079544
references.citation: J Clin Invest. 2009 Sep;119(9):2634-47
references.pmid: 19690389
references.citation: Circulation. 2007 Jul 24;116(4):385-91
references.pmid: 17620507
references.citation: Clin Sci (Lond). 2012 Aug 1;123(3):161-71
references.pmid: 22364258
references.citation: Biochem Biophys Res Commun. 2010 Apr 9;394(3):792-7
references.pmid: 20230787
references.citation: Circ Res. 2011 Sep 2;109(6):697-711
references.pmid: 21885837
references.citation: J Biol Chem. 2010 Aug 13;285(33):25221-31
references.pmid: 20551325
references.citation: Circ Res. 2011 Aug 19;109(5):564-77
references.pmid: 21852555
references.citation: Circ Res. 2010 Sep 3;107(5):677-84
references.pmid: 20595655
references.citation: Atherosclerosis. 2008 Aug;199(2):271-7
references.pmid: 18179800
references.citation: Thrombosis. 2012;2012:306263
references.pmid: 22577539
references.citation: PLoS One. 2012;7(4):e35877
references.pmid: 22558252
references.citation: J Biol Chem. 2011 Sep 23;286(38):33701-6
references.pmid: 21835914
references.citation: Circ Res. 2010 Jul 9;107(1):138-43
references.pmid: 20489163
references.citation: Nutr Metab Cardiovasc Dis. 2012 Nov;22(11):937-43
references.pmid: 22748605
references.citation: J Clin Endocrinol Metab. 2012 Jul;97(7):E1213-8
references.pmid: 22535975
references.citation: Nat Cell Biol. 2011 Apr;13(4):423-33
references.pmid: 21423178
references.citation: Tissue Eng Part B Rev. 2009 Sep;15(3):307-17
references.pmid: 19450137
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5003-8
references.pmid: 21383194
references.citation: Clin Sci (Lond). 2010 Jul 09;119(8):335-43
references.pmid: 20528768
references.citation: Arthritis Rheum. 2011 Jun;63(6):1582-90
references.pmid: 21425254
references.citation: Circulation. 2012 May 8;125(18):2243-55
references.pmid: 22492635
references.citation: Am J Nephrol. 2011;34(3):211-9
references.pmid: 21791917
references.citation: Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2589-96
references.pmid: 17932314
references.citation: Circ Res. 2009 Jul 17;105(2):158-66
references.pmid: 19542014
references.citation: J Biol Chem. 2010 Jun 4;285(23):17442-52
references.pmid: 20353945
references.citation: Circ Res. 2011 Jun 24;109(1):e1-12
references.pmid: 21566214
references.citation: Atherosclerosis. 2011 Nov;219(1):211-7
references.pmid: 21820659
references.citation: Circ Res. 2012 Feb 3;110(3):483-95
references.pmid: 22302755
references.citation: Thromb Haemost. 2012 Apr;107(4):619-25
references.pmid: 22370758
references.citation: J Cell Mol Med. 2008 Oct;12(5B):2073-82
references.pmid: 18194456
references.citation: J Am Coll Cardiol. 2008 Sep 2;52(10):843-50
references.pmid: 18755348
references.citation: PLoS One. 2011 Feb 24;6(2):e16408
references.pmid: 21383985
references.citation: Immunobiology. 2012 May;217(5):533-9
references.pmid: 21899916
references.citation: Atherosclerosis. 2011 Apr;215(2):286-93
references.pmid: 21310411
references.citation: J Clin Invest. 1993 Apr;91(4):1800-9
references.pmid: 8473518
references.citation: Circ Res. 2006 Nov 10;99(10):1044-59
references.pmid: 17095733
references.citation: Arterioscler Thromb Vasc Biol. 2012 Jan;32(1):123-30
references.pmid: 22034513
references.citation: Am J Pathol. 2010 Jul;177(1):473-80
references.pmid: 20489139
references.citation: Stem Cells. 2010 Feb;28(2):357-64
references.pmid: 20039258
references.citation: Cell Death Differ. 2009 Dec;16(12):1590-8
references.pmid: 19816508
references.citation: J Am Soc Nephrol. 2004 Nov;15(11):2857-67
references.pmid: 15504939
references.citation: Genome Res. 2004 Oct;14(10A):1902-10
references.pmid: 15364901
references.citation: Arterioscler Thromb Vasc Biol. 2001 Dec;21(12):1998-2003
references.pmid: 11742876
references.citation: Nucleic Acids Res. 2010 Jan;38(1):215-24
references.pmid: 19850715
references.citation: Nat Cell Biol. 2012 Feb 12;14(3):249-56
references.pmid: 22327366
references.citation: J Cell Biochem. 2010 Jul 1;110(4):935-47
references.pmid: 20564193
references.citation: Nature. 2011 Jan 20;469(7330):336-42
references.pmid: 21248840
references.citation: Kidney Int. 2011 Feb;79(4):414-22
references.pmid: 20944546
references.citation: Arterioscler Thromb Vasc Biol. 2010 Jun;30(6):1118-26
references.pmid: 20378849
references.citation: Am J Physiol Heart Circ Physiol. 2009 Aug;297(2):H802-10
references.pmid: 19542489
references.citation: Circ Cardiovasc Genet. 2011 Dec;4(6):605-13
references.pmid: 22010139
references.citation: Curr Biol. 2010 Oct 12;20(19):R858-61
references.pmid: 20937476
references.citation: Nat Rev Cardiol. 2010 Sep;7(9):528-36
references.pmid: 20664518
references.citation: J Virol. 2011 Dec;85(24):12844-54
references.pmid: 21976651
references.citation: J Biol Chem. 2009 Jul 17;284(29):19272-9
references.pmid: 19454767
references.citation: Lipids Health Dis. 2012 May 15;11:55
references.pmid: 22587332
references.citation: Dev Cell. 2001 Sep;1(3):423-34
references.pmid: 11702953
references.citation: Cancer Inform. 2011 Feb 17;10:13-29
references.pmid: 21552493
references.citation: PLoS One. 2011;6(9):e24145
references.pmid: 21909417
references.citation: J Am Heart Assoc. 2012 Dec;1(6):e003905
references.pmid: 23316327
references.citation: Circ Res. 2011 Oct 28;109(10):1115-9
references.pmid: 21903938
references.citation: Nat Cell Biol. 2007 Jun;9(6):654-9
references.pmid: 17486113
references.citation: Methods. 2013 Jan;59(1):S1-6
references.pmid: 23036329
references.citation: J Cell Biochem. 2010 Apr 1;109(5):866-75
references.pmid: 20039311
references.citation: Am J Physiol Heart Circ Physiol. 2012 Sep 1;303(5):H523-32
references.pmid: 22796540
references.citation: Am J Pathol. 2011 Oct;179(4):1594-600
references.pmid: 21806957
references.citation: Circulation. 2012 Jun 5;125(22):2772-81
references.pmid: 22665885
references.citation: Circ Res. 2013 Jun 21;113(1):72-7
references.pmid: 23616621
references.citation: Nature. 1998 Jan 22;391(6665):357-62
references.pmid: 9450748
references.citation: Sci Signal. 2009 Dec 08;2(100):ra81
references.pmid: 19996457
references.citation: Eur J Endocrinol. 2012 Mar;166(3):359-71
references.pmid: 22084154
references.citation: Cell. 2009 Jan 23;136(2):215-33
references.pmid: 19167326
references.citation: Cardiovasc Res. 2011 Apr 1;90(1):165-70
references.pmid: 21156821
references.citation: J Biol Chem. 2012 Jul 27;287(31):25706-14
references.pmid: 22679022
references.citation: J Thorac Cardiovasc Surg. 2012 Jul;144(1):256-62
references.pmid: 22336757
references.citation: Kidney Int. 2012 Feb;81(3):280-92
references.pmid: 21975861
references.citation: Acta Diabetol. 2011 Mar;48(1):61-9
references.pmid: 20857148
references.citation: Nature. 2004 Sep 16;431(7006):350-5
references.pmid: 15372042
references.citation: Circ Res. 2010 Jul 23;107(2):271-82
references.pmid: 20489161
references.citation: J Cell Biochem. 2009 Sep 1;108(1):216-24
references.pmid: 19565563
references.citation: J Am Heart Assoc. 2012 Oct;1(5):e000745
references.pmid: 23316282
references.citation: J Heart Valve Dis. 2010 Jul;19(4):459-65
references.pmid: 20845893
references.citation: PLoS One. 2012;7(4):e34641
references.pmid: 22506038
references.citation: Biochem Biophys Res Commun. 2010 Mar 19;393(4):643-8
references.pmid: 20153722
references.citation: Nature. 2009 Aug 6;460(7256):705-10
references.pmid: 19578358
references.citation: J Bone Miner Res. 2008 Nov;23(11):1798-805
references.pmid: 18597635
references.citation: Circ Res. 2010 Sep 17;107(6):810-7
references.pmid: 20651284
references.citation: Lab Invest. 2012 Sep;92(9):1250-9
references.pmid: 22688076
references.citation: J Biomech. 2013 Jan 18;46(2):396-401
references.pmid: 23218838
references.citation: Eur Heart J. 2010 Aug;31(16):1975-84
references.pmid: 20601388
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14678-83
references.pmid: 17003118
references.citation: Nucleic Acids Res. 2010 Nov;38(20):7248-59
references.pmid: 20615901
references.citation: Cardiovasc Res. 2012 Jun 1;94(3):545-54
references.pmid: 22436847
references.citation: J Biol Chem. 2008 May 30;283(22):15319-27
references.pmid: 18378684
references.citation: PLoS One. 2012;7(10):e47807
references.pmid: 23094093
references.citation: Mol Cell Biochem. 2011 May;351(1-2):197-205
references.pmid: 21249428
references.citation: Circ Res. 2011 May 27;108(11):1381-91
references.pmid: 21617135
references.citation: PLoS One. 2010 Oct 20;5(10):e13515
references.pmid: 20976003
references.citation: Calcif Tissue Int. 2012 Jun;90(6):473-80
references.pmid: 22527202
references.citation: Eur J Biochem. 2000 Dec;267(24):6954-67
references.pmid: 11106403
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9863-8
references.pmid: 21628588
references.citation: Nephrol Dial Transplant. 2011 Nov;26(11):3794-802
references.pmid: 21891774
references.citation: Am J Physiol Heart Circ Physiol. 2012 Sep 1;303(5):H619-28
references.pmid: 22777419
references.citation: PLoS One. 2011;6(10):e25946
references.pmid: 22022480
references.citation: Circulation. 2009 Apr 7;119(13):1785-94
references.pmid: 19307473
references.citation: Clin Chim Acta. 2011 Jan 14;412(1-2):66-70
references.pmid: 20888330
references.citation: Clin Sci (Lond). 2010 Jul 23;119(9):395-405
references.pmid: 20524934
references.citation: Circ Res. 2012 Aug 17;111(5):543-52
references.pmid: 22773442
references.citation: Stroke. 2011 Sep;42(9):2556-63
references.pmid: 21817153
references.citation: J Vasc Res. 2004 Mar-Apr;41(2):193-201
references.pmid: 15031603
references.citation: Cardiovasc Res. 2012 Nov 1;96(2):320-9
references.pmid: 22871591
references.citation: Clin Orthop Relat Res. 1995 May;(314):266-80
references.pmid: 7634645
references.citation: Circulation. 2007 Dec 11;116(24):2841-50
references.pmid: 18040026
references.citation: Nucleic Acids Res. 2011 Sep 1;39(16):7223-33
references.pmid: 21609964
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10355-60
references.pmid: 21636785
references.citation: Arterioscler Thromb Vasc Biol. 2012 Nov;32(11):2580-8
references.pmid: 22995515
references.citation: J Mol Cell Cardiol. 2012 Jul;53(1):64-72
references.pmid: 22525256