title: MicroRNA-29 in aortic dilation: implications for aneurysm formation.
abstract: BACKGROUND
  Aging represents a major risk factor for coronary artery disease and aortic aneurysm formation. MicroRNAs (miRs) have emerged as key regulators of biological processes, but their role in age-associated vascular pathologies is unknown.
  
  
  OBJECTIVE
  We aim to identify miRs in the vasculature that are regulated by age and play a role in age-induced vascular pathologies.
  
  
  RESULTS
  Expression profiling of aortic tissue of young versus old mice identified several age-associated miRs. Among the significantly regulated miRs, the increased expression of miR-29 family members was associated with a profound downregulation of numerous extracellular matrix (ECM) components in aortas of aged mice, suggesting that this miR family contributes to ECM loss, thereby sensitizing the aorta for aneurysm formation. Indeed, miR-29 expression was significantly induced in 2 experimental models for aortic dilation: angiotensin II-treated aged mice and genetically induced aneurysms in Fibulin-4(R/R) mice. More importantly, miR-29b levels were profoundly increased in biopsies of human thoracic aneurysms, obtained from patients with either bicuspid (n=79) or tricuspid aortic valves (n=30). Finally, LNA-modified antisense oligonucleotide-mediated silencing of miR-29 induced ECM expression and inhibited angiotensin II-induced dilation of the aorta in mice.
  
  
  CONCLUSIONS
  In conclusion, miR-29-mediated downregulation of ECM proteins may sensitize the aorta to the formation of aneurysms in advanced age. Inhibition of miR-29 in vivo abrogates aortic dilation in mice, suggesting that miR-29 may represent a novel molecular target to augment matrix synthesis and maintain vascular wall structural integrity.
authors: Institute for Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Theodor Stern-Kai 7, 60590 Frankfurt, Germany.
authors: Reinier A
authors: RA
authors: Boon
authors: Timon
authors: T
authors: Seeger
authors: Susanne
authors: S
authors: Heydt
authors: Ariane
authors: A
authors: Fischer
authors: Eduard
authors: E
authors: Hergenreider
authors: Anton J G
authors: AJ
authors: Horrevoets
authors: Manlio
authors: M
authors: Vinciguerra
authors: Nadia
authors: N
authors: Rosenthal
authors: Sergio
authors: S
authors: Sciacca
authors: Michele
authors: M
authors: Pilato
authors: Paula
authors: P
authors: van Heijningen
authors: Jeroen
authors: J
authors: Essers
authors: Ralf P
authors: RP
authors: Brandes
authors: Andreas M
authors: AM
authors: Zeiher
authors: Stefanie
authors: S
authors: Dimmeler
mesh_terms: D000375:Aging / Q000235:genetics; D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001014:Aortic Aneurysm / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D001706:Biopsy; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000032:analysis* / Q000378:metabolism*; D009154:Mutation; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; C547014:MIRN29 microRNA, mouse; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D020320:Oligoribonucleotides, Antisense; D000804:Angiotensin II