Sirolimus and paclitaxel provoke different vascular pathological responses after local delivery in a murine model for restenosis on underlying atherosclerotic arteries.
BACKGROUND
Drug-eluting stents (DES) have been introduced successfully in clinical practice to prevent post-angioplasty restenosis. Nevertheless, concerns about the safety of DES still exist.


OBJECTIVE
To investigate the vascular pathology and transcriptional responses to sirolimus and paclitaxel in a murine model for restenosis on underlying diseased atherosclerotic arteries.


METHODS
Atherosclerotic lesions were induced by placement of a perivascular cuff around the femoral artery of hypercholesterolaemic ApoE*3-Leiden transgenic mice. Two weeks later these cuffs were replaced either by sirolimus- or paclitaxel-eluting cuffs. The vascular pathological effects were evaluated after two additional weeks.


RESULTS
Both anti-restenotic compounds significantly inhibited restenotic lesion progression on the atherosclerotic plaques. Vascular histopathological analyses showed that local delivery of sirolimus has no significant adverse effects on vascular disease. Conversely, high dosages of paclitaxel significantly increased apoptosis, internal elastic lamina disruption, and decreased medial and intimal smooth muscle cells and collagen content. Moreover, transcriptional analysis by real-time RT-PCR showed an increased level of pro-apoptotic mRNA transcripts (FAS, BAX, caspase 3) in paclitaxel-treated arteries.


CONCLUSIONS
Sirolimus and paclitaxel are effective in preventing restenosis. Sirolimus has no significant effect on arterial disease. In contrast, paclitaxel at high concentration demonstrated adverse vascular pathology and transcriptional responses, suggesting a narrower therapeutic range of this potent drug. Since the use of overlapping stents is becoming more common in DES technology, this factor is important, given that higher dosages of paclitaxel may lead to increased apoptosis in the vessel wall and, consequently, to a more unstable phenotype of the pre-existing atherosclerotic lesion.
Pires
Nuno M M
NM
TNO-Quality of Life, Gaubius Laboratory, Leiden, The Netherlands.
Eefting
Daniel
D
de Vries
Margreet R
MR
Quax
Paul H A
PH
Jukema
J Wouter
JW
D000199:Actins / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000032:analysis; D004343:Drug Implants; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D007090:Image Interpretation, Computer-Assisted; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000601:surgery; D017239:Paclitaxel / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000627:therapeutic use*; D015607:Stents; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology* / Q000601:surgery
D000199:Actins; D004343:Drug Implants; D012333:RNA, Messenger; D003094:Collagen; D017239:Paclitaxel; D020123:Sirolimus