Inhibition of mTOR down-regulates scavenger receptor, class B, type I (SR-BI) expression, reduces endothelial cell migration and impairs nitric oxide production

Biochim Biophys Acta. 2014 Jul;1841(7):944-53. doi: 10.1016/j.bbalip.2014.03.014. Epub 2014 Apr 5.


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.

Keywords: Cell migration; Endothelial cell; HDL; SR-BI; eNOS; mTOR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antibiotics, Antineoplastic / pharmacology*
  • Biological Transport / drug effects
  • Cell Movement / drug effects
  • Cholesterol, HDL / metabolism
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Molecular Sequence Data
  • Nitric Oxide / antagonists & inhibitors*
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • Scavenger Receptors, Class B / antagonists & inhibitors
  • Scavenger Receptors, Class B / genetics*
  • Scavenger Receptors, Class B / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism


  • Antibiotics, Antineoplastic
  • Cholesterol, HDL
  • RNA, Messenger
  • SCARB1 protein, human
  • Scavenger Receptors, Class B
  • Nitric Oxide
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Sirolimus