Targeted deletions of cyclooxygenase-2 and atherogenesis in mice

Yiqun Hui, Emanuela Ricciotti, Irene Crichton, Zhou Yu, Dairong Wang, Jane Stubbe, Miao Wang, Ellen Puré, Garret A FitzGerald

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

BACKGROUND: Although the dominant product of vascular Cyclooxygenase-2 (COX-2), prostacyclin (PGI(2)), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX-2 in macrophages and T cells (TCs) to atherogenesis. METHODS AND RESULTS: Deletion of macrophage-COX-2 (Mac-COX-2KOs) was attained with LysMCre mice and completely suppressed lipopolysaccharide-stimulated macrophage prostaglandin (PG) formation and lipopolysaccharide-evoked systemic PG biosynthesis by approximately 30%. Lipopolysaccharide-stimulated COX-2 expression was suppressed in polymorphonuclear leukocytes isolated from MacKOs, but PG formation was not even detected in polymorphonuclear leukocyte supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic low-density lipoprotein receptor knockouts. Deletion of Mac-COX-2 appeared to remove a restraint on COX-2 expression in lesional nonleukocyte (CD45- and CD11b-negative) vascular cells that express vascular cell adhesion molecule and variably alpha-smooth muscle actin and vimentin, portending a shift in PG profile and consequent atheroprotection. Basal expression of COX-2 was minimal in TCs, but use of CD4Cre to generate TC knockouts depressed its modest upregulation by anti-CD3epsilon. However, biosynthesis of PGs, TC composition in lymphatic organs, and atherogenesis in low-density lipoprotein receptor knockouts were unaltered in TC knockouts. CONCLUSIONS: Macrophage-COX-2, primarily a source of thromboxane A(2) and prostaglandin (PG)E(2), promotes atherogenesis and exerts a restraint on enzyme expression by lesional cells suggestive of vascular smooth muscle cells, a prominent source of atheroprotective prostacyclin. TC COX-2 does not detectably influence TC development or function or atherogenesis in mice.
OriginalsprogEngelsk
TidsskriftCirculation
Vol/bind121
Udgave nummer24
Sider (fra-til)2654-60
Antal sider7
ISSN0009-7322
DOI
StatusUdgivet - 22. jun. 2010

Fingeraftryk

Macrophages
LDL Receptors
Epoprostenol
Neutrophils
Vascular Cell Adhesion Molecule-1
Vimentin
Vascular Smooth Muscle
Smooth Muscle
Actins
Up-Regulation
Enzymes

Citer dette

Hui, Y., Ricciotti, E., Crichton, I., Yu, Z., Wang, D., Stubbe, J., ... FitzGerald, G. A. (2010). Targeted deletions of cyclooxygenase-2 and atherogenesis in mice. Circulation, 121(24), 2654-60. https://doi.org/10.1161/CIRCULATIONAHA.109.910687
Hui, Yiqun ; Ricciotti, Emanuela ; Crichton, Irene ; Yu, Zhou ; Wang, Dairong ; Stubbe, Jane ; Wang, Miao ; Puré, Ellen ; FitzGerald, Garret A. / Targeted deletions of cyclooxygenase-2 and atherogenesis in mice. I: Circulation. 2010 ; Bind 121, Nr. 24. s. 2654-60.
@article{3713fdb4d5a042eea05e849967571749,
title = "Targeted deletions of cyclooxygenase-2 and atherogenesis in mice",
abstract = "BACKGROUND: Although the dominant product of vascular Cyclooxygenase-2 (COX-2), prostacyclin (PGI(2)), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX-2 in macrophages and T cells (TCs) to atherogenesis. METHODS AND RESULTS: Deletion of macrophage-COX-2 (Mac-COX-2KOs) was attained with LysMCre mice and completely suppressed lipopolysaccharide-stimulated macrophage prostaglandin (PG) formation and lipopolysaccharide-evoked systemic PG biosynthesis by approximately 30{\%}. Lipopolysaccharide-stimulated COX-2 expression was suppressed in polymorphonuclear leukocytes isolated from MacKOs, but PG formation was not even detected in polymorphonuclear leukocyte supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic low-density lipoprotein receptor knockouts. Deletion of Mac-COX-2 appeared to remove a restraint on COX-2 expression in lesional nonleukocyte (CD45- and CD11b-negative) vascular cells that express vascular cell adhesion molecule and variably alpha-smooth muscle actin and vimentin, portending a shift in PG profile and consequent atheroprotection. Basal expression of COX-2 was minimal in TCs, but use of CD4Cre to generate TC knockouts depressed its modest upregulation by anti-CD3epsilon. However, biosynthesis of PGs, TC composition in lymphatic organs, and atherogenesis in low-density lipoprotein receptor knockouts were unaltered in TC knockouts. CONCLUSIONS: Macrophage-COX-2, primarily a source of thromboxane A(2) and prostaglandin (PG)E(2), promotes atherogenesis and exerts a restraint on enzyme expression by lesional cells suggestive of vascular smooth muscle cells, a prominent source of atheroprotective prostacyclin. TC COX-2 does not detectably influence TC development or function or atherogenesis in mice.",
keywords = "Animals, Atherosclerosis, Cells, Cultured, Cyclooxygenase 2, Disease Models, Animal, Female, Gene Deletion, Macrophages, Male, Mice, Mice, Knockout, Prostaglandins, RNA, Messenger, Receptors, LDL, T-Lymphocytes",
author = "Yiqun Hui and Emanuela Ricciotti and Irene Crichton and Zhou Yu and Dairong Wang and Jane Stubbe and Miao Wang and Ellen Pur{\'e} and FitzGerald, {Garret A}",
year = "2010",
month = "6",
day = "22",
doi = "10.1161/CIRCULATIONAHA.109.910687",
language = "English",
volume = "121",
pages = "2654--60",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams & Wilkins",
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}

Hui, Y, Ricciotti, E, Crichton, I, Yu, Z, Wang, D, Stubbe, J, Wang, M, Puré, E & FitzGerald, GA 2010, 'Targeted deletions of cyclooxygenase-2 and atherogenesis in mice', Circulation, bind 121, nr. 24, s. 2654-60. https://doi.org/10.1161/CIRCULATIONAHA.109.910687

Targeted deletions of cyclooxygenase-2 and atherogenesis in mice. / Hui, Yiqun; Ricciotti, Emanuela; Crichton, Irene; Yu, Zhou; Wang, Dairong; Stubbe, Jane; Wang, Miao; Puré, Ellen; FitzGerald, Garret A.

I: Circulation, Bind 121, Nr. 24, 22.06.2010, s. 2654-60.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Targeted deletions of cyclooxygenase-2 and atherogenesis in mice

AU - Hui, Yiqun

AU - Ricciotti, Emanuela

AU - Crichton, Irene

AU - Yu, Zhou

AU - Wang, Dairong

AU - Stubbe, Jane

AU - Wang, Miao

AU - Puré, Ellen

AU - FitzGerald, Garret A

PY - 2010/6/22

Y1 - 2010/6/22

N2 - BACKGROUND: Although the dominant product of vascular Cyclooxygenase-2 (COX-2), prostacyclin (PGI(2)), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX-2 in macrophages and T cells (TCs) to atherogenesis. METHODS AND RESULTS: Deletion of macrophage-COX-2 (Mac-COX-2KOs) was attained with LysMCre mice and completely suppressed lipopolysaccharide-stimulated macrophage prostaglandin (PG) formation and lipopolysaccharide-evoked systemic PG biosynthesis by approximately 30%. Lipopolysaccharide-stimulated COX-2 expression was suppressed in polymorphonuclear leukocytes isolated from MacKOs, but PG formation was not even detected in polymorphonuclear leukocyte supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic low-density lipoprotein receptor knockouts. Deletion of Mac-COX-2 appeared to remove a restraint on COX-2 expression in lesional nonleukocyte (CD45- and CD11b-negative) vascular cells that express vascular cell adhesion molecule and variably alpha-smooth muscle actin and vimentin, portending a shift in PG profile and consequent atheroprotection. Basal expression of COX-2 was minimal in TCs, but use of CD4Cre to generate TC knockouts depressed its modest upregulation by anti-CD3epsilon. However, biosynthesis of PGs, TC composition in lymphatic organs, and atherogenesis in low-density lipoprotein receptor knockouts were unaltered in TC knockouts. CONCLUSIONS: Macrophage-COX-2, primarily a source of thromboxane A(2) and prostaglandin (PG)E(2), promotes atherogenesis and exerts a restraint on enzyme expression by lesional cells suggestive of vascular smooth muscle cells, a prominent source of atheroprotective prostacyclin. TC COX-2 does not detectably influence TC development or function or atherogenesis in mice.

AB - BACKGROUND: Although the dominant product of vascular Cyclooxygenase-2 (COX-2), prostacyclin (PGI(2)), restrains atherogenesis, inhibition and deletion of COX-2 have yielded conflicting results in mouse models of atherosclerosis. Floxed mice were used to parse distinct cellular contributions of COX-2 in macrophages and T cells (TCs) to atherogenesis. METHODS AND RESULTS: Deletion of macrophage-COX-2 (Mac-COX-2KOs) was attained with LysMCre mice and completely suppressed lipopolysaccharide-stimulated macrophage prostaglandin (PG) formation and lipopolysaccharide-evoked systemic PG biosynthesis by approximately 30%. Lipopolysaccharide-stimulated COX-2 expression was suppressed in polymorphonuclear leukocytes isolated from MacKOs, but PG formation was not even detected in polymorphonuclear leukocyte supernatants from control mice. Atherogenesis was attenuated when MacKOs were crossed into hyperlipidemic low-density lipoprotein receptor knockouts. Deletion of Mac-COX-2 appeared to remove a restraint on COX-2 expression in lesional nonleukocyte (CD45- and CD11b-negative) vascular cells that express vascular cell adhesion molecule and variably alpha-smooth muscle actin and vimentin, portending a shift in PG profile and consequent atheroprotection. Basal expression of COX-2 was minimal in TCs, but use of CD4Cre to generate TC knockouts depressed its modest upregulation by anti-CD3epsilon. However, biosynthesis of PGs, TC composition in lymphatic organs, and atherogenesis in low-density lipoprotein receptor knockouts were unaltered in TC knockouts. CONCLUSIONS: Macrophage-COX-2, primarily a source of thromboxane A(2) and prostaglandin (PG)E(2), promotes atherogenesis and exerts a restraint on enzyme expression by lesional cells suggestive of vascular smooth muscle cells, a prominent source of atheroprotective prostacyclin. TC COX-2 does not detectably influence TC development or function or atherogenesis in mice.

KW - Animals

KW - Atherosclerosis

KW - Cells, Cultured

KW - Cyclooxygenase 2

KW - Disease Models, Animal

KW - Female

KW - Gene Deletion

KW - Macrophages

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Prostaglandins

KW - RNA, Messenger

KW - Receptors, LDL

KW - T-Lymphocytes

U2 - 10.1161/CIRCULATIONAHA.109.910687

DO - 10.1161/CIRCULATIONAHA.109.910687

M3 - Journal article

VL - 121

SP - 2654

EP - 2660

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 24

ER -