title: MicroRNA-93 controls perfusion recovery after hindlimb ischemia by modulating expression of multiple genes in the cell cycle pathway.
abstract: BACKGROUND
  MicroRNAs are key regulators of gene expression in response to injury, but there is limited knowledge of their role in ischemia-induced angiogenesis, such as in peripheral arterial disease. Here, we used an unbiased strategy and took advantage of different phenotypic outcomes that follow surgically induced hindlimb ischemia between inbred mouse strains to identify key microRNAs involved in perfusion recovery from hindlimb ischemia.
  
  
  RESULTS
  From comparative microRNA profiling between inbred mouse strains that display profound differences in their extent of perfusion recovery after hindlimb ischemia, we found that the mouse strain with higher levels of microRNA-93 (miR-93) in hindlimb muscle before ischemia and the greater ability to upregulate miR-93 in response to ischemia had better perfusion recovery. In vitro, overexpression of miR-93 attenuated hypoxia-induced apoptosis in both endothelial and skeletal muscle cells and enhanced proliferation in both cell types. In addition, miR-93 overexpression enhanced endothelial cell tube formation. In vivo, miR-93 overexpression enhanced capillary density and perfusion recovery from hindlimb ischemia, and antagomirs to miR-93 attenuated perfusion recovery. Both in vitro and in vivo modulation of miR-93 resulted in alterations in the expression of >1 cell cycle pathway gene in 2 different cell types.
  
  
  CONCLUSIONS
  Our data indicate that miR-93 enhances perfusion recovery from hindlimb ischemia by modulation of multiple genes that coordinate the functional pathways of cell proliferation and apoptosis. Thus, miR-93 is a strong potential target for pharmacological modulation to promote angiogenesis in ischemic tissue.
authors.affiliation: Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Surovi
authors.initials: S
authors.lastname: Hazarika
authors.forename: Charles R
authors.initials: CR
authors.lastname: Farber
authors.forename: Ayotunde O
authors.initials: AO
authors.lastname: Dokun
authors.forename: Achillieas N
authors.initials: AN
authors.lastname: Pitsillides
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: R John
authors.initials: RJ
authors.lastname: Lye
authors.forename: Brian H
authors.initials: BH
authors.lastname: Annex
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006614:Hindlimb / Q000098:blood supply* / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D020127:Recovery of Function / Q000502:physiology*; D015424:Reperfusion / Q000379:methods
chemical_list: D035683:MicroRNAs; C551470:Mirn93 microRNA, mouse
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):11015-20
references.pmid: 16835303
references.citation: J Biol Chem. 2012 Jun 22;287(26):21783-95
references.pmid: 22547075
references.citation: Cancer Res. 2008 Oct 15;68(20):8191-4
references.pmid: 18922889
references.citation: Mol Cell Biol. 2008 Apr;28(7):2167-74
references.pmid: 18212054
references.citation: Mol Cancer. 2011 May 28;10:65
references.pmid: 21619671
references.citation: Nat Rev Genet. 2004 Jul;5(7):522-31
references.pmid: 15211354
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: FEBS Lett. 2012 May 7;586(9):1279-86
references.pmid: 22465665
references.citation: J Biol Chem. 2010 Jul 23;285(30):23457-65
references.pmid: 20501654
references.citation: Oncogene. 2011 Feb 17;30(7):806-21
references.pmid: 20956944
references.citation: Arterioscler Thromb Vasc Biol. 2006 Mar;26(3):520-6
references.pmid: 16397137
references.citation: Nat Med. 2011 Jan;17(1):71-8
references.pmid: 21186368
references.citation: Annu Rev Biomed Eng. 2010 Aug 15;12:1-27
references.pmid: 20415587
references.citation: Mol Cell. 2011 Jun 10;42(5):700-12
references.pmid: 21658608
references.citation: Circ Res. 2007 Oct 26;101(9):948-56
references.pmid: 17823371
references.citation: Blood. 2005 Jan 15;105(2):659-69
references.pmid: 15374877
references.citation: Cancer. 1999 Nov 15;86(10):2021-33
references.pmid: 10570427
references.citation: Nature. 2005 Dec 1;438(7068):685-9
references.pmid: 16258535
references.citation: Cell. 2008 Mar 7;132(5):875-86
references.pmid: 18329372
references.citation: Oncogene. 2008 Mar 13;27(12):1788-93
references.pmid: 17891175
references.citation: Diabetes. 2007 Mar;56(3):656-65
references.pmid: 17327433
references.citation: Physiol Genomics. 2007 Jul 18;30(2):179-91
references.pmid: 17426116
references.citation: Circulation. 2011 Mar 8;123(9):999-1009
references.pmid: 21339483
references.citation: Cancer Sci. 2009 Jul;100(7):1234-42
references.pmid: 19486339
references.citation: Lancet Oncol. 2010 Feb;11(2):136-46
references.pmid: 20022810
references.citation: J Biol Chem. 2012 Aug 3;287(32):27055-64
references.pmid: 22692216
references.citation: Bioinformatics. 2007 Aug 15;23(16):2183-4
references.pmid: 17586828
references.citation: J Biol Chem. 2005 Mar 11;280(10):9330-5
references.pmid: 15613470
references.citation: Circulation. 2008 Mar 4;117(9):1207-15
references.pmid: 18285563
references.citation: Mol Cell Biol. 1994 Dec;14(12):8166-73
references.pmid: 7969153
references.citation: Oncogene. 2009 Sep 24;28(38):3360-70
references.pmid: 19597470
references.citation: Science. 2009 Jun 26;324(5935):1710-3
references.pmid: 19460962
references.citation: J Cell Biol. 2011 Jan 10;192(1):69-81
references.pmid: 21200031
references.citation: J Biol Chem. 1999 Mar 19;274(12):8039-45
references.pmid: 10075703