title: miR-17 targets tissue inhibitor of metalloproteinase 1 and 2 to modulate cardiac matrix remodeling.
abstract: We aimed to investigate the role of miR-17 in cardiac matrix remodeling following myocardial infarction (MI). Using real-time PCR, we quantified endogenous miR-17 in infarcted mouse hearts. Compared with related microRNAs, miR-17 was up-regulated most dramatically: 3.7-fold and 2.4-fold in the infarct region 3 and 7 d post-MI, respectively, and 2.4-fold in the border zone at d 3 compared to sham control (P<0.01). Chimeric luciferase reporter constructs were cloned for miR-17 target validation. miR-17 targeted the 3'-UTR of TIMP2 and the protein coding region of TIMP1. The miR-17 mimic decreased TIMP2 (P<0.01) and TIMP1 (P<0.05) protein expression compared with the scrambled control. Inhibition of endogenous miR-17 by in vivo antagomir delivery enhanced TIMP2 (P<0.01) and TIMP1 (P<0.05) protein expression compared to the mismatch group, decreased MMP9 activity (P<0.05), reduced infarct size as early as 7 d post-MI (P<0.05), and improved cardiac function (fractional shortening and fractional area contraction, P<0.05) at d 21 and 28 post-MI. Transgenic mice overexpressing miR-17 in the heart confirmed the deleterious role of miR-17 in matrix modulation. Our study suggests that miR-17 participates in the regulation of cardiac matrix remodeling and provides a novel therapeutic approach using miR-17 inhibitors to prevent remodeling and heart failure after MI.
authors.affiliation: 1University Health Network, Toronto Medical Discovery Tower, MaRS Centre, Rm. 3-702, 101 College St., Toronto, ON, Canada, M5G 1L7. renkeli@uhnres.utoronto.ca.
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Sun
authors.forename: Mihan
authors.initials: M
authors.lastname: Han
authors.forename: Sze Wan
authors.initials: SW
authors.lastname: Shan
authors.forename: Zhaoqun
authors.initials: Z
authors.lastname: Deng
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009841:Oligonucleotides; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling
chemical_list: D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; D009841:Oligonucleotides; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2
keywords: MMP; TIMP1; TIMP2; myocardial infarction