Intramural delivery of Sirolimus prevents vascular remodeling following balloon injury.
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).
Buerke
Michael
M
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
Guckenbiehl
Markus
M
Schwertz
Hansjörg
H
Buerke
Ute
U
Hilker
Michael
M
Platsch
Herbert
H
Richert
Joachim
J
Bomm
Sabine
S
Zimmerman
Guy A
GA
Lindemann
Stephan
S
Mueller-Werdan
Ursula
U
Werdan
Karl
K
Darius
Harald
H
Weyrich
Andrew S
AS
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
D000199:Actins; D024061:Collagen Type III; D005353:Fibronectins; D007797:Laminin; D014746:Vimentin; D000515:alpha 1-Antitrypsin; C084098:laminin A; D020123:Sirolimus