The impact of immunosuppression on endothelial function.
Endothelial dysfunction is an early marker for transplant atherosclerosis. Potential mechanisms for allograft endothelial dysfunction include stimulation of alloimmune-dependent pathways, ischemia/reperfusion injury, metabolic alterations, chronic infections, as well as direct endothelial cell activation by immunosuppressive drugs. Thus far, no study has directly compared different immunosuppressive drugs with respect to their potential to modulate endothelial function under normoxic and hypoxic conditions. We examined human microvascular endothelial cells (HMEC-1) in vitro after stimulation with therapeutic concentrations of methylprednisolone (MP), mycophenolic acid (MMF), cyclosporine A (CS), rapamycin (Rapa), and tacrolimus (Tac) to designate the corresponding induction of oxidative stress, apoptosis, metabolic activity, proliferation, endothelin (ET-1) release, and nitric oxide (NO) production. HMEC-1 stimulation with CS, MMF, and Rapa resulted in a stronger induction of oxidative stress compared with MP and Tac. Induction of oxidative stress by immunosuppressives correlated with metabolic activity and apoptosis. Low- and high-dose MMF significantly inhibited cell proliferation under hypoxic conditions, whereas low-dose CS and MP increased endothelial cell proliferation. ET-1 release was significantly elevated by Rapa, Tac, and MP. NO production was significantly enhanced by all immunosuppressive drugs except Tac. Quality and quantity of immunosuppression modify endothelial function and lead to a dose-dependent and oxygenation-state-related endothelial activation. MP and MMF induced minor changes in endothelial function compared with CS, Rapa, and Tac.
Trapp
Anja
A
Medizinische Klinik und Poliklinik I, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University of Munich, Munich, Germany.
Weis
Michael
M
D017209:Apoptosis; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D008833:Microcirculation; D009569:Nitric Oxide / Q000096:biosynthesis; D018384:Oxidative Stress
D019332:Endothelin-1; D007166:Immunosuppressive Agents; D009569:Nitric Oxide