title: Prevention of abdominal aortic aneurysm by anti-microRNA-712 or anti-microRNA-205 in angiotensin II-infused mice.
abstract: OBJECTIVE
  Abdominal aortic aneurysm (AAA) is characterized as a progressive dilation and degradation of the aortic wall, associated with activation of matrix metalloproteinases (MMPs) and inflammation. Emerging evidence indicates a role for microRNAs (miRNAs) in AAA pathogenesis, but it is unclear whether abdominal aortic endothelial miRNAs play a role in the disease process. We aimed to identify miRNAs in the abdominal aortic endothelium that play a critical role in AAA development.
  
  
  RESULTS
  The mouse model of AAA induced by angiotensin II infusion was used in this study. Through a miRNA array and validation study, we initially identified the murine-specific miR-712 and subsequently its human/murine homolog miR-205 as angiotensin II-induced miRNAs in the abdominal aortic endothelium in vivo and in vitro. Mechanistically, miR-712 stimulated MMP activity in the aortic wall by directly targeting 2 MMP inhibitors: tissue inhibitor of metalloproteinase 3 (TIMP3) and reversion-inducing cysteine-rich protein with kazal motifs (RECK). Silencing of miR-712 and miR-205 by using anti-miR-712 and anti-miR-205, respectively, significantly decreased the aortic MMP activity and inflammation, preventing AAA development in angiotensin II-infused ApoE(-/-) mice. Further, upregulation of 4 angiotensin II-sensitive miRNAs, miR-205, -21, -133b, and -378, identified in this murine study were confirmed in human AAA samples compared with nondiseased control.
  
  
  CONCLUSIONS
  Our results demonstrate that angiotensin II-sensitive miR-712 and its human homolog miR-205 downregulate TIMP3 and RECK, which in turn stimulate aortic MMP activity and inflammation, leading to AAA development. Targeting these miRNAs may be a novel therapeutic strategy to prevent AAA.
authors.affiliation: From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (C.W.K., S.K., D.J.S., I.-H.J., H.J.); and Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA (C.W.K., S.K., D.J.S., I.-H.J., K.K.G., H.J.).
authors.forename: Chan Woo
authors.initials: CW
authors.lastname: Kim
authors.affiliation: From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (C.W.K., S.K., D.J.S., I.-H.J., H.J.); and Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA (C.W.K., S.K., D.J.S., I.-H.J., K.K.G., H.J.).
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.affiliation: From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (C.W.K., S.K., D.J.S., I.-H.J., H.J.); and Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA (C.W.K., S.K., D.J.S., I.-H.J., K.K.G., H.J.).
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.affiliation: From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (C.W.K., S.K., D.J.S., I.-H.J., H.J.); and Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA (C.W.K., S.K., D.J.S., I.-H.J., K.K.G., H.J.).
authors.forename: In-Hwan
authors.initials: IH
authors.lastname: Jang
authors.affiliation: From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (C.W.K., S.K., D.J.S., I.-H.J., H.J.); and Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA (C.W.K., S.K., D.J.S., I.-H.J., K.K.G., H.J.).
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Griendling
authors.affiliation: From the Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (C.W.K., S.K., D.J.S., I.-H.J., H.J.); and Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA (C.W.K., S.K., D.J.S., I.-H.J., K.K.G., H.J.). hjo@bme.gatech.edu.
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
mesh_terms: D000328:Adult; D000368:Aged; D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism*; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D013997:Time Factors; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000804:Angiotensin II; D001057:Apolipoproteins E; D058851:GPI-Linked Proteins; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D019717:Tissue Inhibitor of Metalloproteinase-3; C534425:MIR205, human; C576666:MIRN205 microRNA, mouse; C531950:MIRN21 microRNA, mouse; C546119:MIRN378 microRNA, mouse; C000589250:MIRN712 microRNA, human; C000589251:MIRN712 microRNA, mouse; C517732:Mirn133 microRNA, mouse; C492025:Reck protein, mouse
keywords: TIMP3; abdominal aortic aneurysm; angiotensin II; microRNA