Rapamycin reduces neointima formation during vascular injury.
BACKGROUND
Proliferation and migration of vascular smooth muscle cells (SMCs) mark the key processes in the development of bypass graft disease and during neointima formation in restenosis after angioplasty. Growth factors are potent SMC mitogens as they are involved in SMC proliferation and in extracellular matrix (ECM) synthesis. Based on these premises, we examined the effect of the proliferation inhibitor rapamycin in human SMC culture and in a rabbit vascular injury model.


METHODS
Injection of rapamycin or its vehicle was performed with an infusion-balloon catheter directly into the vessel wall during vascular injury. The intima/media ratio was determined histologically whereas the protein expression was analysed using the powerful two-dimensional gel electrophoresis (2D page) technique. Inhibition of proliferation after rapamycin application was estimated in a human SMC culture for time and dose dependent effects.


RESULTS
Rapamycin treatment resulted in a significant reduction of intima media ratio compared to vehicle treated animals after three weeks (0.65 +/- 0.1 vs. 1.2 +/- 0.2 intima-media-ratio, p < 0.05). 2D electrophoresis analysis proved increased ECM synthesis following angioplasty (i.e., lamin, vimentin) in vehicle treated animals. Local rapamycin administration resulted in profound reduction of ECM synthesis after vascular injury. In in-vitro experiments exposure of cultured human SMCs to rapamycin resulted in a significant and dose-dependent (1 nm-100 nm) reduction of human smooth muscle cell proliferation measured by cell counting.


CONCLUSIONS
These above mentioned results suggest that protein synthesis in addition to reduction of cellular proliferation plays an important role following vascular injury, since application of rapamycin resulted in the reduction of SMC proliferation and ECM-synthesis.
Hilker
M
M
Department of Thoracic and Cardiovascular Surgery, Johannes Gutenberg University, Mainz, Germany. hilker@mail.uni-mainz.de
Buerke
M
M
Guckenbiehl
M
M
Schwertz
H
H
Bühler
J
J
Moersig
W
W
Hake
U
U
Oelert
H
H
D000800:Angioplasty, Balloon; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D005352:Fibromuscular Dysplasia / Q000473:pathology*; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D011817:Rabbits; D020123:Sirolimus / Q000494:pharmacology*; D017540:Tunica Media / Q000187:drug effects* / Q000473:pathology
D009124:Muscle Proteins; D020123:Sirolimus