title: Intramural delivery of Sirolimus prevents vascular remodeling following balloon injury.
abstract: OBJECTIVE
  Several studies have demonstrated that Sirolimus-eluting stents reduce restenosis in patients with coronary artery disease. Here, we tested whether direct delivery of Sirolimus into the vessel wall during balloon angioplasty can modify vascular remodeling over several weeks.
  
  
  RESULTS
  During angioplasty of the rabbit iliac artery we administered an intramural infusion of Sirolimus or its vehicle directly through a balloon catheter into the vessel wall. After 3 weeks neointimal formation was decreased (0.71+/-0.1 vs. 1.4+/-0.12 intima/media ratio), and this process was attributed to the inhibitory properties of Sirolimus on ECM deposition and smooth muscle cell proliferation. Sirolimus also significantly reduced the deposition of elastin, collagen III and fibronectin within the vascular wall. In parallel, proteomic profiles of arterial wall segments were obtained and 485 protein spots were consistently matched between non-dilated and dilated vessels. Differential expression of 12 proteins were observed between the groups and direct sequencing of digested peptides was performed. Local delivery of sirolimus during angioplasty attenuated the expression of structural proteins that included lamin A, vimentin, alpha-1-antitrypsin, and alpha-actin.
  
  
  CONCLUSIONS
  Local administration of Sirolimus during angioplasty prevents smooth muscle cell proliferation associated with vascular remodeling as well as the expression of extracellular matrix and structural proteins. Therefore, local injection of Sirolimus during balloon inflation may be an alternative therapeutic approach for preventing restenosis in small stenotic vessels (i.e., <2.5 mm).
authors.affiliation: Department of Medicine III, Martin-Luther-University, Ernst-Grube-Str. 40, 06097 Halle, and Department of Cardiology, Neu-Kölln-Hospital, Berlin, Germany. michael.buerke@medizin.uni-halle.de
authors.forename: Michael
authors.initials: M
authors.lastname: Buerke
authors.forename: Markus
authors.initials: M
authors.lastname: Guckenbiehl
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schwertz
authors.forename: Ute
authors.initials: U
authors.lastname: Buerke
authors.forename: Michael
authors.initials: M
authors.lastname: Hilker
authors.forename: Herbert
authors.initials: H
authors.lastname: Platsch
authors.forename: Joachim
authors.initials: J
authors.lastname: Richert
authors.forename: Sabine
authors.initials: S
authors.lastname: Bomm
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
authors.forename: Stephan
authors.initials: S
authors.lastname: Lindemann
authors.forename: Ursula
authors.initials: U
authors.lastname: Mueller-Werdan
authors.forename: Karl
authors.initials: K
authors.lastname: Werdan
authors.forename: Harald
authors.initials: H
authors.lastname: Darius
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Weyrich
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000800:Angioplasty, Balloon; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D024061:Collagen Type III / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000187:drug effects; D005353:Fibronectins / Q000096:biosynthesis; D006083:Graft Occlusion, Vascular / Q000517:prevention & control; D007083:Iliac Artery / Q000378:metabolism; D007797:Laminin / Q000096:biosynthesis; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D011817:Rabbits; D020123:Sirolimus / Q000008:administration & dosage*; D017539:Tunica Intima / Q000473:pathology; D014746:Vimentin / Q000096:biosynthesis; D000515:alpha 1-Antitrypsin / Q000096:biosynthesis
chemical_list: D000199:Actins; D024061:Collagen Type III; D005353:Fibronectins; D007797:Laminin; D014746:Vimentin; D000515:alpha 1-Antitrypsin; C084098:laminin A; D020123:Sirolimus