Neointimal expression of rapamycin receptor FK506-binding protein FKBP12: postinjury animal and human in-stent restenosis tissue characteristics.
Despite excellent clinical results for sirolimus (rapamycin)-eluting stents, the exact mechanisms of antirestenotic activity and affected cellular targets are incompletely understood. Therefore, we determined the presence and tem- porospatial expression pattern of FKBP12, the primary intracellular receptor of rapamycin, in rat carotid arteries after balloon injury, as well as in human in-stent restenosis and primary stable coronary atheroma. FKBP12 expression was assessed by immunohistochemistry. Rat carotid arteries revealed maximal expression in 57.7 +/- 4.0% of neointimal cells at day 7. A large proportion of these FKBP12+ cells showed luminally confined co-expression with dendritic cell markers. Despite a considerably thicker neointima at day 28, presence of FKBP12 decreased (8.5 +/- 1.9%, p = 0.02) with a scattered pattern in luminal and deep neointima. Likewise, human in-stent restenosis atherectomy specimens (time after stent implantation 2-12 months) revealed a comparable extent of cellular rapamycin receptor expression (9.3 +/- 1.0%) that significantly differed from that found in primary stable atheroma (1.3 +/- 0.4%, p < 0.001). In conclusion, the rapamycin receptor is predominantly present during early neointima formation, while mature neointimal atheromas show a relatively low expression without confinement to luminal areas. Co-expression of FKBP12 and dendritic cell markers suggests that dendritic cells may be another important target for early and long-term rapamycin effects.
Bauriedel
Gerhard
G
Department of Internal Medicine II - Cardiology, University of Bonn, Bonn, Germany. g.bauriedel.med1@klinikum-meiningen.de
Jabs
Alexander
A
Kraemer
Stefan
S
Nickenig
Georg
G
Skowasch
Dirk
D
D000368:Aged; D000818:Animals; D017225:Atherectomy, Coronary; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D020212:Carotid Artery Injuries / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects; D023903:Coronary Restenosis / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D023921:Coronary Stenosis / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D054855:Drug-Eluting Stents; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage*; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism*; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D002317:Cardiovascular Agents; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus