title: Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development.
abstract: MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe-/- mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti-miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Maegdefessel
authors.forename: Junya
authors.initials: J
authors.lastname: Azuma
authors.forename: Ryuji
authors.initials: R
authors.lastname: Toh
authors.forename: Denis R
authors.initials: DR
authors.lastname: Merk
authors.forename: Alicia
authors.initials: A
authors.lastname: Deng
authors.forename: Jocelyn T
authors.initials: JT
authors.lastname: Chin
authors.forename: Uwe
authors.initials: U
authors.lastname: Raaz
authors.forename: Anke M
authors.initials: AM
authors.lastname: Schoelmerich
authors.forename: Azad
authors.initials: A
authors.lastname: Raiesdana
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Leeper
authors.forename: Michael V
authors.initials: MV
authors.lastname: McConnell
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Dalman
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.forename: Philip S
authors.initials: PS
authors.lastname: Tsao
mesh_terms: D000293:Adolescent; D000368:Aged; D017542:Aneurysm, Ruptured / Q000517:prevention & control*; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; 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; D010196:Pancreatic Elastase / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013552:Swine; D055815:Young Adult
chemical_list: D001057:Apolipoproteins E; C547014:MIRN29 microRNA, mouse; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D020033:Protein Isoforms; D000804:Angiotensin II; D003094:Collagen; D004549:Elastin; D010196:Pancreatic Elastase