mTOR-inhibitors simultaneously inhibit proliferation and basal IL-6 synthesis of human coronary artery endothelial cells.
Divergent results regarding the immunosuppressive effects of mammalian-target-of-rapamycin-(mTOR)-inhibitors on venous endothelial cells (ECs) have highlighted the importance of an accurate EC-model. The purpose of this study was to determine mTOR-inhibitor effects at a specific site of action -- the human coronary-artery-ECs (HCAECs) -- and to compare these data with results gained from cultures of human saphenous vein ECs (HSVECs). This EC-model could enable us to gain insight into site-specific pharmacodynamics and the immunosuppressive management of transplant vasculopathy. ECs were cultivated with rising concentrations of mTOR-inhibitors in the presence/absence of tumor necrosis factor (TNF). Cell counts, DNA-synthesis, cytotoxicity and concentrations of the cytokine IL-6 as well as the chemokines IL-8 and MCP-1 were measured. Half-maximal inhibitory effects on cell growth were reached after about 30 h incubation and both cell types showed equal responses regarding cell growth and DNA-synthesis after 48 h incubation time. mTOR-inhibitors failed to suppress basal/TNF-induced secretion of IL-8 and MCP-1, but IL-6 synthesis after TNF-induction was reduced to 35%. In contrast to human saphenous vein ECs (HSVECs), mTOR-inhibitors also reduced basal IL-6-secretion of HCAECs (to 55%) and cell proliferation was simultaneously inhibited within the same concentration range. Taking everything into account, we conclude that EC-proliferation is inhibited at concentrations needed to suppress TNF-stimulated IL-6 synthesis. Furthermore, the specific suppression of basal arterial IL-6-secretion and the delayed onset of the mTOR-inhibitor effect on HCAEC-proliferation (maximum reached after about 36 h) might be of relevance for the prevention of transplant vasculopathy at its initial stage, e.g. as a component of cardioplegic solutions.
Schreml
Stephan
S
Clinic of Cardiothoracic Surgery, University of Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg, Germany. stephan.schreml@web.de
Lehle
Karla
K
Birnbaum
Dietrich E
DE
Preuner
Jürgen G
JG
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D011494:Protein Kinases / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012501:Saphenous Vein / Q000166:cytology; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D016207:Cytokines; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus