mTOR inhibitors and calcineurin inhibitors do not affect adhesion molecule expression of human macro- and microvascular endothelial cells.
We examined the effect of cyclosporin A, tacrolimus, sirolimus and everolimus on the cell growth, viability, proliferation, expression of cellular adhesion molecules (CAM) and leukocyte (PBMC) binding of human macrovascular (coronary artery, saphenous vein) and microvascular endothelial cells (EC). Tacrolimus did not affect EC integrity, growth or expression of CAM. Exclusively, EC from the coronary arteries showed a reduced cellular growth (about 30%) under cyclosporin A and tacrolimus treatment. In contrast, treatment with mTOR inhibitors reduced EC proliferative activity by about 40%, independently of the EC origin. No induction of apoptosis (caspase-3/7 activity) or cytotoxicity (MTS test) was observed. Long-term treatment with high concentrations of sirolimus and everolimus did not enhance the expression of CAM. Stimulation with tumor necrosis factor significantly increased the expression of CAM, independently of the drugs used. None of the mTOR inhibitors influenced the tumor necrosis factor-induced expression of CAM, whereas adhesion of PBMC increased significantly, as described by other papers. In summary, neither calcineurin inhibitors nor mTOR inhibitors activate human micro- and macrovascular EC. Therefore, the investigated drugs are unlikely to contribute to EC activation during transplant-associated vasculopathy.
Lehle
Karla
K
Department of Cardiothoracic Surgery, University of Regensburg, Regensburg, Germany. karla.lehle@klinik.uni-regensburg.de
Schreml
Stephan
S
Kunz-Schughart
Leoni A
LA
Rupprecht
Leopold
L
Birnbaum
Dietrich E
DE
Schmid
Christof
C
Preuner
Jürgen G
JG
D001808:Blood Vessels / Q000166:cytology*; D065095:Calcineurin Inhibitors; D002196:Capillaries / Q000166:cytology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D042783:Endothelial Cells / Q000737:chemistry* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000737:chemistry* / Q000378:metabolism; D000068338:Everolimus; D006801:Humans; D011494:Protein Kinases / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D015815:Cell Adhesion Molecules; D016572:Cyclosporine; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D016559:Tacrolimus