Inhibition of mTOR down-regulates scavenger receptor, class B, type I (SR-BI) expression, reduces endothelial cell migration and impairs nitric oxide production.
The mammalian target of rapamycin (mTOR) inhibiting drug rapamycin (Sirolimus) has severe side effects in patients including hyperlipidemia, an established risk factor for atherosclerosis. Recently, it was shown that rapamycin decreases hepatic LDL receptor (LDL-R) expression, which likely contributes to hypercholesterolemia. Scavenger receptor, class B, type I (SR-BI) is the major HDL receptor and consequently regulating HDL-cholesterol levels and the athero-protective effects of HDL. By using the mTOR inhibitor rapamycin, we show that SR-BI is down-regulated in human umbilical vein endothelial cells (HUVECs). This reduction of SR-BI protein as well as mRNA levels by about 50% did not alter HDL particle uptake or HDL-derived lipid transfer. However, rapamycin reduced HDL-induced activation of eNOS and stimulation of endothelial cell migration. The effects on cell migration could be counteracted by SR-BI overexpression, indicating that decreased SR-BI expression is in part responsible for the rapamycin-induced effects. We demonstrate that inhibition of mTOR leads to endothelial cell dysfunction and decreased SR-BI expression, which may contribute to atherogenesis during rapamycin treatment.
Institute of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
Stefanie
S
Fruhwürth
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
Sigurd
S
Krieger
Institute of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
Katharina
K
Winter
Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
Margit
M
Rosner
Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
Mario
M
Mikula
Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
Thomas
T
Weichhart
Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, NY, USA.
Robert
R
Bittman
Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
Markus
M
Hengstschläger
Institute of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria. Electronic address: herbert.stangl@meduniwien.ac.at.
Herbert
H
Stangl
D000595:Amino Acid Sequence; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D008076:Cholesterol, HDL / Q000378:metabolism; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D008076:Cholesterol, HDL; D012333:RNA, Messenger; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Cell migration; Endothelial cell; HDL; SR-BI; eNOS; mTOR