PMID- 26752047
OWN - NLM
STAT- MEDLINE
DCOM- 20160719
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 1
DP  - 2016
TI  - Rapamycin Inhibits Oxidized Low Density Lipoprotein Uptake in Human Umbilical 
      Vein Endothelial Cells via mTOR/NF-kappaB/LOX-1 Pathway.
PG  - e0146777
LID - 10.1371/journal.pone.0146777 [doi]
LID - e0146777
AB  - BACKGROUND: Lectin-like oxidized low-density lipoprotein-1 (LOX-1) is the major 
      receptor for oxidized low density lipoprotein (ox-LDL) uptake in human umbilical 
      vein endothelial cells (HUVECs). Previously, we found that rapamycin inhibited 
      ox-LDL accumulation in HUVECs, and this effect was related to its role in 
      increasing the activity of autophagy-lysosome pathway. In this study, we 
      determined whether rapamycin could also reduce ox-LDL uptake in HUVECs and 
      investigated the underlying signaling mechanisms. RESULTS: Flow cytometry and 
      live cell imaging showed that rapamycin reduced Dil-ox-LDL accumulation in 
      HUVECs. Furthermore, rapamycin reduced the ox-LDL-induced increase in LOX-1 mRNA 
      and protein levels. Western blotting showed that rapamycin inhibited mechanistic 
      target of rapamycin (mTOR), p70s6k and IkappaBalpha phosphorylation triggered by ox-LDL. 
      Flow cytometry implied that mTOR, NF-kappaB knockdown and NF-kappaB inhibitors 
      significantly reduced Dil-ox-LDL uptake. Moreover, immunofluorescent staining 
      showed that rapamycin reduced the accumulation of p65 in the nucleus after ox-LDL 
      treatment for 30 h. mTOR knockdown decreased LOX-1 protein production and IkappaBalpha 
      phosphorylation induced by ox-LDL. NF-kappaB knockdown and NF-kappaB inhibitors reduced 
      LOX-1 protein production, but did not inhibit mTOR phosphorylation stimulated by 
      ox-LDL. CONCLUSIONS: These findings demonstrate that rapamycin reduce mTOR 
      phosphorylation and subsequently inhibit NF-kappaB activation and suppresses LOX-1, 
      resulting in a reduction in ox-LDL uptake in HUVECs.
FAU - Zhou, Yan-De
AU  - Zhou YD
AD  - Department of Endocrinology, The Second Affiliated Hospital of Soochow 
      University, Suzhou, Jiangsu, China.
FAU - Cao, Xue-Qin
AU  - Cao XQ
AD  - Department of Endocrinology, The Second Affiliated Hospital of Soochow 
      University, Suzhou, Jiangsu, China.
FAU - Liu, Zhi-Hua
AU  - Liu ZH
AD  - Department of Endocrinology, The Second Affiliated Hospital of Soochow 
      University, Suzhou, Jiangsu, China.
FAU - Cao, Yong-Jun
AU  - Cao YJ
AD  - Department of Neurology, The Second Affiliated Hospital of Soochow University, 
      Suzhou, Jiangsu, China.
FAU - Liu, Chun-Feng
AU  - Liu CF
AD  - Department of Neurology, The Second Affiliated Hospital of Soochow University, 
      Suzhou, Jiangsu, China.
AD  - Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, China.
FAU - Zhang, Yan-Lin
AU  - Zhang YL
AD  - Department of Neurology, The Second Affiliated Hospital of Soochow University, 
      Suzhou, Jiangsu, China.
FAU - Xie, Ying
AU  - Xie Y
AD  - Department of Endocrinology, The Second Affiliated Hospital of Soochow 
      University, Suzhou, Jiangsu, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160111
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Lipoproteins, LDL)
RN  - 0 (NF-kappa B p50 Subunit)
RN  - 0 (NFKB1 protein, human)
RN  - 0 (OLR1 protein, human)
RN  - 0 (Scavenger Receptors, Class E)
RN  - 0 (oxidized low density lipoprotein)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Atherosclerosis/metabolism
MH  - Autophagy/drug effects
MH  - Cell Nucleus/metabolism
MH  - Cell Proliferation
MH  - Disease Progression
MH  - Gene Expression Regulation, Enzymologic
MH  - Human Umbilical Vein Endothelial Cells/metabolism
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology
MH  - Lipoproteins, LDL/*pharmacokinetics
MH  - Lysosomes/metabolism
MH  - NF-kappa B p50 Subunit/*metabolism
MH  - Phosphorylation
MH  - Scavenger Receptors, Class E/*metabolism
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Transfection
PMC - PMC4709184
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2016/01/12 06:00
MHDA- 2016/07/20 06:00
PMCR- 2016/01/11
CRDT- 2016/01/12 06:00
PHST- 2015/05/10 00:00 [received]
PHST- 2015/12/22 00:00 [accepted]
PHST- 2016/01/12 06:00 [entrez]
PHST- 2016/01/12 06:00 [pubmed]
PHST- 2016/07/20 06:00 [medline]
PHST- 2016/01/11 00:00 [pmc-release]
AID - PONE-D-15-20265 [pii]
AID - 10.1371/journal.pone.0146777 [doi]
PST - epublish
SO  - PLoS One. 2016 Jan 11;11(1):e0146777. doi: 10.1371/journal.pone.0146777. 
      eCollection 2016.