Coinhibition of mTORC1/mTORC2 and RhoA /ROCK pathways prevents chronic rejection of rat cardiac allografts

Wei Chen; Wenhao Chen; Xian C. Li; Rafik M. Ghobrial; Malgorzata Kloc

doi:10.1016/j.tpr.2018.09.002

Coinhibition of mTORC1/mTORC2 and RhoA /ROCK pathways prevents chronic rejection of rat cardiac allografts

Wei Chen, Wenhao Chen, Xian C. Li, Rafik M. Ghobrial, Malgorzata Kloc

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Chronic rejection of transplanted organs remains an unresolved issue in clinical organ transplantation. The macrophages play a crucial role in the development of chronic rejection. We showed previously that macrophage-specific deletion of RhoA or RhoA/ROCK inhibition prevent macrophage movement to the cardiac allografts and abrogate chronic rejection in rodent transplantation models. Here we assessed the ability of the mTORC1 and mTORC2 inhibitor everolimus, alone or in conjunction with the RhoA/ROCK inhibitor Y27632, to inhibit chronic rejection of Wistar Furth (WF; RT1.A^u) rat cardiac allografts heterotopically transplanted into ACI (RT1.A^a) recipients. The transplanted hearts were analyzed for vessel occlusion and tissue fibrosis. T cell and macrophage subsets infiltration was analyzed by immunostaining with T cell and macrophage molecular markers. We found that a combination of the mTOR inhibitor everolimus and the RhoA/ROCK inhibitor Y27632 prolonged allograft survival; decreased vessel occlusion, collagen deposition, and macrophage infiltration; and inhibited the chronic rejection of rat cardiac allografts. These results indicate that coinhibition of the mTORC1/mTORC2 and RhoA pathways in transplant recipients abrogates chronic rejection of rat cardiac allografts, and will aid in the development of clinically applicable anti-chronic rejection therapies.

Original language	English (US)
Pages (from-to)	21-28
Number of pages	8
Journal	Transplantation Reports
Volume	3
Issue number	4
DOIs	https://doi.org/10.1016/j.tpr.2018.09.002
State	Published - Dec 2018

Keywords

Abbreviations: Arg1, Arginase 1
Chronic rejection
Everolimus
HRP, horseradish peroxidase
M1, pro-inflammatory macrophage subtype
M2, anti-inflammatory macrophage subtype
ROCK
ROCK [ROCK1 and ROCK 2], p160ROCK, a Rho-associated, coiled-coil-containing protein kinase
Rac1, Ras-Related C3 Botulinum Toxin Substrate 1
Rat
RhoA
RhoA, Ras homolog gene family, member A
Rictor, Rapamycin-insensitive companion of mammalian target of rapamycin
Transplantation
VVG, Verhoeff-Van Gieson [VVG], a stain for elastic fibers
Y27632
Y27632, Y-27632 2HCl, a selective inhibitor of ROCK1 [p160ROCK] kinase
iNos, inducible nitric oxide synthase
mTOR, mechanistic target of rapamycin, also known as mammalian target of rapamycin or FK506-binding protein 12-rapamycin-associated protein 1 [FRAP1], a kinase that is a member of the phosphatidylinositol 3-kinase-related protein kinase family.
mTORC1, mammalian target of rapamycin complex 1
mTORC1/mTORC2
mTORC2, rapamycin-insensitive mTOR complex 2

ASJC Scopus subject areas

Surgery
Transplantation

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10.1016/j.tpr.2018.09.002

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@article{72917ccce2d94e4bbba77608ef75c051,

title = "Coinhibition of mTORC1/mTORC2 and RhoA /ROCK pathways prevents chronic rejection of rat cardiac allografts",

abstract = "Chronic rejection of transplanted organs remains an unresolved issue in clinical organ transplantation. The macrophages play a crucial role in the development of chronic rejection. We showed previously that macrophage-specific deletion of RhoA or RhoA/ROCK inhibition prevent macrophage movement to the cardiac allografts and abrogate chronic rejection in rodent transplantation models. Here we assessed the ability of the mTORC1 and mTORC2 inhibitor everolimus, alone or in conjunction with the RhoA/ROCK inhibitor Y27632, to inhibit chronic rejection of Wistar Furth (WF; RT1.Au) rat cardiac allografts heterotopically transplanted into ACI (RT1.Aa) recipients. The transplanted hearts were analyzed for vessel occlusion and tissue fibrosis. T cell and macrophage subsets infiltration was analyzed by immunostaining with T cell and macrophage molecular markers. We found that a combination of the mTOR inhibitor everolimus and the RhoA/ROCK inhibitor Y27632 prolonged allograft survival; decreased vessel occlusion, collagen deposition, and macrophage infiltration; and inhibited the chronic rejection of rat cardiac allografts. These results indicate that coinhibition of the mTORC1/mTORC2 and RhoA pathways in transplant recipients abrogates chronic rejection of rat cardiac allografts, and will aid in the development of clinically applicable anti-chronic rejection therapies.",

keywords = "Abbreviations: Arg1, Arginase 1, Chronic rejection, Everolimus, HRP, horseradish peroxidase, M1, pro-inflammatory macrophage subtype, M2, anti-inflammatory macrophage subtype, ROCK, ROCK [ROCK1 and ROCK 2], p160ROCK, a Rho-associated, coiled-coil-containing protein kinase, Rac1, Ras-Related C3 Botulinum Toxin Substrate 1, Rat, RhoA, RhoA, Ras homolog gene family, member A, Rictor, Rapamycin-insensitive companion of mammalian target of rapamycin, Transplantation, VVG, Verhoeff-Van Gieson [VVG], a stain for elastic fibers, Y27632, Y27632, Y-27632 2HCl, a selective inhibitor of ROCK1 [p160ROCK] kinase, iNos, inducible nitric oxide synthase, mTOR, mechanistic target of rapamycin, also known as mammalian target of rapamycin or FK506-binding protein 12-rapamycin-associated protein 1 [FRAP1], a kinase that is a member of the phosphatidylinositol 3-kinase-related protein kinase family., mTORC1, mammalian target of rapamycin complex 1, mTORC1/mTORC2, mTORC2, rapamycin-insensitive mTOR complex 2",

author = "Wei Chen and Wenhao Chen and Li, {Xian C.} and Ghobrial, {Rafik M.} and Malgorzata Kloc",

note = "Funding Information: We are grateful for the support from Novartis . Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2018",

month = dec,

doi = "10.1016/j.tpr.2018.09.002",

language = "English (US)",

volume = "3",

pages = "21--28",

journal = "Transplantation Reports",

issn = "2451-9596",

publisher = "Elsevier",

number = "4",

}

TY - JOUR

T1 - Coinhibition of mTORC1/mTORC2 and RhoA /ROCK pathways prevents chronic rejection of rat cardiac allografts

AU - Chen, Wei

AU - Chen, Wenhao

AU - Li, Xian C.

AU - Ghobrial, Rafik M.

AU - Kloc, Malgorzata

PY - 2018/12

Y1 - 2018/12

N2 - Chronic rejection of transplanted organs remains an unresolved issue in clinical organ transplantation. The macrophages play a crucial role in the development of chronic rejection. We showed previously that macrophage-specific deletion of RhoA or RhoA/ROCK inhibition prevent macrophage movement to the cardiac allografts and abrogate chronic rejection in rodent transplantation models. Here we assessed the ability of the mTORC1 and mTORC2 inhibitor everolimus, alone or in conjunction with the RhoA/ROCK inhibitor Y27632, to inhibit chronic rejection of Wistar Furth (WF; RT1.Au) rat cardiac allografts heterotopically transplanted into ACI (RT1.Aa) recipients. The transplanted hearts were analyzed for vessel occlusion and tissue fibrosis. T cell and macrophage subsets infiltration was analyzed by immunostaining with T cell and macrophage molecular markers. We found that a combination of the mTOR inhibitor everolimus and the RhoA/ROCK inhibitor Y27632 prolonged allograft survival; decreased vessel occlusion, collagen deposition, and macrophage infiltration; and inhibited the chronic rejection of rat cardiac allografts. These results indicate that coinhibition of the mTORC1/mTORC2 and RhoA pathways in transplant recipients abrogates chronic rejection of rat cardiac allografts, and will aid in the development of clinically applicable anti-chronic rejection therapies.

AB - Chronic rejection of transplanted organs remains an unresolved issue in clinical organ transplantation. The macrophages play a crucial role in the development of chronic rejection. We showed previously that macrophage-specific deletion of RhoA or RhoA/ROCK inhibition prevent macrophage movement to the cardiac allografts and abrogate chronic rejection in rodent transplantation models. Here we assessed the ability of the mTORC1 and mTORC2 inhibitor everolimus, alone or in conjunction with the RhoA/ROCK inhibitor Y27632, to inhibit chronic rejection of Wistar Furth (WF; RT1.Au) rat cardiac allografts heterotopically transplanted into ACI (RT1.Aa) recipients. The transplanted hearts were analyzed for vessel occlusion and tissue fibrosis. T cell and macrophage subsets infiltration was analyzed by immunostaining with T cell and macrophage molecular markers. We found that a combination of the mTOR inhibitor everolimus and the RhoA/ROCK inhibitor Y27632 prolonged allograft survival; decreased vessel occlusion, collagen deposition, and macrophage infiltration; and inhibited the chronic rejection of rat cardiac allografts. These results indicate that coinhibition of the mTORC1/mTORC2 and RhoA pathways in transplant recipients abrogates chronic rejection of rat cardiac allografts, and will aid in the development of clinically applicable anti-chronic rejection therapies.

KW - Abbreviations: Arg1, Arginase 1

KW - Chronic rejection

KW - Everolimus

KW - HRP, horseradish peroxidase

KW - M1, pro-inflammatory macrophage subtype

KW - M2, anti-inflammatory macrophage subtype

KW - ROCK

KW - ROCK [ROCK1 and ROCK 2], p160ROCK, a Rho-associated, coiled-coil-containing protein kinase

KW - Rac1, Ras-Related C3 Botulinum Toxin Substrate 1

KW - Rat

KW - RhoA

KW - RhoA, Ras homolog gene family, member A

KW - Rictor, Rapamycin-insensitive companion of mammalian target of rapamycin

KW - Transplantation

KW - VVG, Verhoeff-Van Gieson [VVG], a stain for elastic fibers

KW - Y27632

KW - Y27632, Y-27632 2HCl, a selective inhibitor of ROCK1 [p160ROCK] kinase

KW - iNos, inducible nitric oxide synthase

KW - mTOR, mechanistic target of rapamycin, also known as mammalian target of rapamycin or FK506-binding protein 12-rapamycin-associated protein 1 [FRAP1], a kinase that is a member of the phosphatidylinositol 3-kinase-related protein kinase family.

KW - mTORC1, mammalian target of rapamycin complex 1

KW - mTORC1/mTORC2

KW - mTORC2, rapamycin-insensitive mTOR complex 2

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U2 - 10.1016/j.tpr.2018.09.002

DO - 10.1016/j.tpr.2018.09.002

M3 - Article

AN - SCOPUS:85054184640

SN - 2451-9596

VL - 3

SP - 21

EP - 28

JO - Transplantation Reports

JF - Transplantation Reports

IS - 4

ER -

Coinhibition of mTORC1/mTORC2 and RhoA /ROCK pathways prevents chronic rejection of rat cardiac allografts

Abstract

Keywords

ASJC Scopus subject areas

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