title: MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion.
abstract: Identification and treatment of abdominal aortic aneurysm (AAA) remains among the most prominent challenges in vascular medicine. MicroRNAs are crucial regulators of cardiovascular pathology and represent possible targets for the inhibition of AAA expansion. We identified microRNA-21 (miR-21) as a key modulator of proliferation and apoptosis of vascular wall smooth muscle cells during development of AAA in two established murine models. In both models (AAA induced by porcine pancreatic elastase or infusion of angiotensin II), miR-21 expression increased as AAA developed. Lentiviral overexpression of miR-21 induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion. miR-21 overexpression substantially decreased expression of the phosphatase and tensin homolog (PTEN) protein, leading to increased phosphorylation and activation of AKT, a component of a pro-proliferative and antiapoptotic pathway. Systemic injection of a locked nucleic acid-modified antagomir targeting miR-21 diminished the pro-proliferative impact of down-regulated PTEN, leading to a marked increase in the size of AAA. Similar results were seen in mice with AAA augmented by nicotine and in human aortic tissue samples from patients undergoing surgical repair of AAA (with more pronounced effects observed in smokers). Modulation of miR-21 expression shows potential as a new therapeutic option to limit AAA expansion and vascular disease progression.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, 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: Alicia
authors.initials: A
authors.lastname: Deng
authors.forename: Denis R
authors.initials: DR
authors.lastname: Merk
authors.forename: Azad
authors.initials: A
authors.lastname: Raiesdana
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Leeper
authors.forename: Uwe
authors.initials: U
authors.lastname: Raaz
authors.forename: Anke M
authors.initials: AM
authors.lastname: Schoelmerich
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: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000150:complications / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000473:pathology; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010196:Pancreatic Elastase; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034421:Sus scrofa; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015850:Interleukin-6; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D000804:Angiotensin II; D009538:Nicotine; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse; D010196:Pancreatic Elastase