Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis

Vladimir R. Babaev; Joshua D. Chew; Lei Ding; Sarah Davis; Matthew D. Breyer; Richard M. Breyer; John A. Oates; Sergio Fazio; MacRae F. Linton

doi:10.1016/j.cmet.2008.09.005

Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis

Vladimir R. Babaev, Joshua D. Chew, Lei Ding, Sarah Davis, Matthew D. Breyer, Richard M. Breyer, John A. Oates, Sergio Fazio, MacRae F. Linton

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

100 Scopus citations

Abstract

Prostaglandin (PG) E₂, a major product of activated macrophages, has been implicated in atherosclerosis and plaque rupture. The PGE₂ receptors, EP2 and EP4, are expressed in atherosclerotic lesions and are known to inhibit apoptosis in cancer cells. To examine the roles of macrophage EP4 and EP2 in apoptosis and early atherosclerosis, fetal liver cell transplantation was used to generate LDLR^-/- mice chimeric for EP2^-/- or EP4^-/- hematopoietic cells. After 8 weeks on a Western diet, EP4^-/- → LDLR^-/- mice, but not EP2^-/- → LDLR^-/- mice, had significantly reduced aortic atherosclerosis with increased apoptotic cells in the lesions. EP4^-/- peritoneal macrophages had increased sensitivity to proapoptotic stimuli, including palmitic acid and free cholesterol loading, which was accompanied by suppression of activity of p-Akt, p-Bad, and NF-κB-regulated genes. Thus, EP4 deficiency inhibits the PI3K/Akt and NF-κB pathways compromising macrophage survival and suppressing early atherosclerosis, identifying macrophage EP4-signaling pathways as molecular targets for modulating the development of atherosclerosis.

Original language	English (US)
Pages (from-to)	492-501
Number of pages	10
Journal	Cell Metabolism
Volume	8
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2008.09.005
State	Published - Dec 6 2008
Externally published	Yes

Keywords

HUMDISEASE
SIGNALING

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2008.09.005

Cite this

@article{5ceb9d1ca0b849f9ae27ef6c3690094c,

title = "Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis",

abstract = "Prostaglandin (PG) E2, a major product of activated macrophages, has been implicated in atherosclerosis and plaque rupture. The PGE2 receptors, EP2 and EP4, are expressed in atherosclerotic lesions and are known to inhibit apoptosis in cancer cells. To examine the roles of macrophage EP4 and EP2 in apoptosis and early atherosclerosis, fetal liver cell transplantation was used to generate LDLR-/- mice chimeric for EP2-/- or EP4-/- hematopoietic cells. After 8 weeks on a Western diet, EP4-/- → LDLR-/- mice, but not EP2-/- → LDLR-/- mice, had significantly reduced aortic atherosclerosis with increased apoptotic cells in the lesions. EP4-/- peritoneal macrophages had increased sensitivity to proapoptotic stimuli, including palmitic acid and free cholesterol loading, which was accompanied by suppression of activity of p-Akt, p-Bad, and NF-κB-regulated genes. Thus, EP4 deficiency inhibits the PI3K/Akt and NF-κB pathways compromising macrophage survival and suppressing early atherosclerosis, identifying macrophage EP4-signaling pathways as molecular targets for modulating the development of atherosclerosis.",

keywords = "HUMDISEASE, SIGNALING",

author = "Babaev, {Vladimir R.} and Chew, {Joshua D.} and Lei Ding and Sarah Davis and Breyer, {Matthew D.} and Breyer, {Richard M.} and Oates, {John A.} and Sergio Fazio and Linton, {MacRae F.}",

note = "Funding Information: We thank Youmin Zhang and Robert P. Runner for excellent technical expertise. This work was supported by National Institutes of Health grants HL53989, HL65405, HL57986, HL65709, GM15431and DK59637 (Lipid, Lipoprotein and Atherosclerosis Core of the Vanderbilt Mouse Metabolic Phenotype Centers). The EP2 −/− and EP4 −/− mice were developed with the support of DK37097 to R.M.B. and M.B. None of the authors of this paper have a financial interest related to these studies. ",

year = "2008",

month = dec,

day = "6",

doi = "10.1016/j.cmet.2008.09.005",

language = "English (US)",

volume = "8",

pages = "492--501",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis

AU - Babaev, Vladimir R.

AU - Chew, Joshua D.

AU - Ding, Lei

AU - Davis, Sarah

AU - Breyer, Matthew D.

AU - Breyer, Richard M.

AU - Oates, John A.

AU - Fazio, Sergio

AU - Linton, MacRae F.

N1 - Funding Information: We thank Youmin Zhang and Robert P. Runner for excellent technical expertise. This work was supported by National Institutes of Health grants HL53989, HL65405, HL57986, HL65709, GM15431and DK59637 (Lipid, Lipoprotein and Atherosclerosis Core of the Vanderbilt Mouse Metabolic Phenotype Centers). The EP2 −/− and EP4 −/− mice were developed with the support of DK37097 to R.M.B. and M.B. None of the authors of this paper have a financial interest related to these studies.

PY - 2008/12/6

Y1 - 2008/12/6

N2 - Prostaglandin (PG) E2, a major product of activated macrophages, has been implicated in atherosclerosis and plaque rupture. The PGE2 receptors, EP2 and EP4, are expressed in atherosclerotic lesions and are known to inhibit apoptosis in cancer cells. To examine the roles of macrophage EP4 and EP2 in apoptosis and early atherosclerosis, fetal liver cell transplantation was used to generate LDLR-/- mice chimeric for EP2-/- or EP4-/- hematopoietic cells. After 8 weeks on a Western diet, EP4-/- → LDLR-/- mice, but not EP2-/- → LDLR-/- mice, had significantly reduced aortic atherosclerosis with increased apoptotic cells in the lesions. EP4-/- peritoneal macrophages had increased sensitivity to proapoptotic stimuli, including palmitic acid and free cholesterol loading, which was accompanied by suppression of activity of p-Akt, p-Bad, and NF-κB-regulated genes. Thus, EP4 deficiency inhibits the PI3K/Akt and NF-κB pathways compromising macrophage survival and suppressing early atherosclerosis, identifying macrophage EP4-signaling pathways as molecular targets for modulating the development of atherosclerosis.

AB - Prostaglandin (PG) E2, a major product of activated macrophages, has been implicated in atherosclerosis and plaque rupture. The PGE2 receptors, EP2 and EP4, are expressed in atherosclerotic lesions and are known to inhibit apoptosis in cancer cells. To examine the roles of macrophage EP4 and EP2 in apoptosis and early atherosclerosis, fetal liver cell transplantation was used to generate LDLR-/- mice chimeric for EP2-/- or EP4-/- hematopoietic cells. After 8 weeks on a Western diet, EP4-/- → LDLR-/- mice, but not EP2-/- → LDLR-/- mice, had significantly reduced aortic atherosclerosis with increased apoptotic cells in the lesions. EP4-/- peritoneal macrophages had increased sensitivity to proapoptotic stimuli, including palmitic acid and free cholesterol loading, which was accompanied by suppression of activity of p-Akt, p-Bad, and NF-κB-regulated genes. Thus, EP4 deficiency inhibits the PI3K/Akt and NF-κB pathways compromising macrophage survival and suppressing early atherosclerosis, identifying macrophage EP4-signaling pathways as molecular targets for modulating the development of atherosclerosis.

KW - HUMDISEASE

KW - SIGNALING

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AN - SCOPUS:56449095449

SN - 1550-4131

VL - 8

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EP - 501

JO - Cell Metabolism

JF - Cell Metabolism

IS - 6

ER -

Macrophage EP4 Deficiency Increases Apoptosis and Suppresses Early Atherosclerosis

Abstract

Keywords

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