Inhibition of mammalian target of rapamycin modulates expression of adhesion molecules in endothelial cells.
Neointimal hyperplasia often follows angioplasty-induced arterial injury or stenting and results in restenosis. Previous reports have suggested that arterial injury activates complement which amplifies inflammatory responses that may initiate and sustain neointimal hyperplasia. The effects of rapamycin on complement-induced expression of intracellular adhesion molecules (ICAMs) were examined in porcine arterial endothelial cell (PAEC) line that was transformed with large T antigen. Porcine complement was activated by treating sera with zymosan (PO ZYM) to generate C5b-9. C5b-9 binds to PAEC in a concentration- and time-dependent manner. PO ZYM-induced expression of ICAMs was maximally induced by 18h. Rapamycin reduced the expression of vascular cell adhesion molecule (VCAM) and P-selectin in a concentration-dependent manner. Adhesion of monocytes was reduced by rapamycin and the inhibition was prevented by antibodies to vascular cell adhesion molecule, P-selectin and endothelial-leukocyte adhesion molecule (ELAM). In summary, inhibition of the mammalian target of rapamycin down regulates complement-induced ICAMs expression which may modulate inflammatory responses that follow stent implant-induced restenosis during percutanous coronary interventions.
Wood
Steven C
SC
Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, CDRH, FDA, Building 64, Rm 3026, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002, USA. steven.wood@fda.hhs.gov
Bushar
Grace
G
Tesfamariam
Belay
B
D000818:Animals; D001011:Aorta / Q000166:cytology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D013552:Swine; D058570:TOR Serine-Threonine Kinases
D015815:Cell Adhesion Molecules; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus