PMID- 24580843
OWN - NLM
STAT- MEDLINE
DCOM- 20141211
LR  - 20230124
IS  - 1600-6143 (Electronic)
IS  - 1600-6135 (Print)
IS  - 1600-6135 (Linking)
VI  - 14
IP  - 4
DP  - 2014 Apr
TI  - Everolimus inhibits anti-HLA I antibody-mediated endothelial cell signaling, 
      migration and proliferation more potently than sirolimus.
PG  - 806-19
LID - 10.1111/ajt.12669 [doi]
AB  - Antibody (Ab) crosslinking of HLA I molecules on the surface of endothelial cells 
      triggers proliferative and pro-survival intracellular signaling, which is 
      implicated in the process of chronic allograft rejection, also known as 
      transplant vasculopathy (TV). The purpose of this study was to investigate the 
      role of mammalian target of rapamycin (mTOR) in HLA I Ab-induced signaling 
      cascades. Everolimus provides a tool to establish how the mTOR signal network 
      regulates HLA I-mediated migration, proliferation and survival. We found that 
      everolimus inhibits mTOR complex 1 (mTORC1) by disassociating Raptor from mTOR, 
      thereby preventing class I-induced phosphorylation of mTOR, p70S6K, S6RP and 
      4E-BP1, and resultant class I-stimulated cell migration and proliferation. 
      Furthermore, we found that everolimus inhibits class I-mediated mTORC2 activation 
      (1) by disassociating Rictor and Sin1 from mTOR; (2) by preventing class 
      I-stimulated Akt phosphorylation and (3) by preventing class I-mediated ERK 
      phosphorylation. These results suggest that everolimus is more effective than 
      sirolimus at antagonizing both mTORC1 and mTORC2, the latter of which is critical 
      in endothelial cell functional changes leading to TV in solid organ 
      transplantation after HLA I crosslinking. Our findings point to a potential 
      therapeutic effect of everolimus in prevention of chronic Ab-mediated rejection.
CI  - (c) Copyright 2014 The American Society of Transplantation and the American Society 
      of Transplant Surgeons.
FAU - Jin, Y-P
AU  - Jin YP
AD  - Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, 
      University of California, Los Angeles, CA.
FAU - Valenzuela, N M
AU  - Valenzuela NM
FAU - Ziegler, M E
AU  - Ziegler ME
FAU - Rozengurt, E
AU  - Rozengurt E
FAU - Reed, E F
AU  - Reed EF
LA  - eng
GR  - R01 HL090995/HL/NHLBI NIH HHS/United States
GR  - R01 AI 042819/AI/NIAID NIH HHS/United States
GR  - P30 DK041301/DK/NIDDK NIH HHS/United States
GR  - R01 AI042819/AI/NIAID NIH HHS/United States
GR  - T32 HL069766/HL/NHLBI NIH HHS/United States
GR  - 5T32HL069766-12/HL/NHLBI NIH HHS/United States
GR  - U018I077821/PHS HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140301
PL  - United States
TA  - Am J Transplant
JT  - American journal of transplantation : official journal of the American Society of 
      Transplantation and the American Society of Transplant Surgeons
JID - 100968638
RN  - 0 (Antibodies)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Multiprotein Complexes)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antibodies/immunology/*pharmacology
MH  - Aorta/cytology/*immunology/metabolism
MH  - Blotting, Western
MH  - Cell Movement/*drug effects
MH  - Cell Proliferation/*drug effects
MH  - Cells, Cultured
MH  - Endothelium, Vascular/cytology/*immunology/metabolism
MH  - Everolimus
MH  - Histocompatibility Antigens Class I/*immunology
MH  - Humans
MH  - Immunoprecipitation
MH  - Immunosuppressive Agents/pharmacology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Multiprotein Complexes/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*analogs & derivatives/*pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Wound Healing
PMC - PMC5555744
MID - NIHMS891326
OTO - NOTNLM
OT  - Endothelial cells
OT  - HLA
OT  - everolimus
OT  - mTOR
OT  - signal transduction
OT  - transplantation
COIS- DISCLOSURE The authors of this manuscript have conflicts of interest to disclose 
      as described by the American Journal of Transplantation. This study was supported 
      by the Novartis Investigator Initiated Research Grant.
EDAT- 2014/03/04 06:00
MHDA- 2014/12/17 06:00
PMCR- 2017/08/14
CRDT- 2014/03/04 06:00
PHST- 2013/07/29 00:00 [received]
PHST- 2014/01/13 00:00 [revised]
PHST- 2014/01/14 00:00 [accepted]
PHST- 2014/03/04 06:00 [entrez]
PHST- 2014/03/04 06:00 [pubmed]
PHST- 2014/12/17 06:00 [medline]
PHST- 2017/08/14 00:00 [pmc-release]
AID - S1600-6135(22)25407-0 [pii]
AID - 10.1111/ajt.12669 [doi]
PST - ppublish
SO  - Am J Transplant. 2014 Apr;14(4):806-19. doi: 10.1111/ajt.12669. Epub 2014 Mar 1.