Lack of EP4 receptors on bone marrow-derived cells enhances inflammation in atherosclerotic lesions.
OBJECTIVE
prostaglandin E(2), by ligation of its receptor EP4, suppresses the production of inflammatory cytokines and chemokines in macrophages in vitro. Thus, activation of EP4 may constitute an endogenous anti-inflammatory pathway. This study investigated the role of EP4 in atherosclerosis in vivo, and particularly its impact on inflammation.


RESULTS
Ldlr(-/-) mice transplanted with EP4(+/+) or EP4(-/-) bone marrow consumed a high-fat diet for 5 or 10 weeks. Allogenic bone marrow transplantation promoted exacerbation of atherosclerosis irrespective of EP4 genotype, compatible with prior observations of exacerbated atherogenesis by allogenicity. EP4 deficiency had little effect on plaque size or morphology in early atherosclerosis, but at the later time point, mice deficient in EP4 displayed enhanced inflammation in their atherosclerotic plaques. Expression of monocyte chemoattractant protein-1 and interferon-γ inducible protein 10 increased, and there was a corresponding increase in macrophage and T-cell infiltration. These plaques also contained fewer smooth muscle cells. Despite these changes, mice deficient in EP4 in bone marrow-derived cells at an advanced stage had similar lesion size (in both aorta and aortic root) as mice with EP4.


CONCLUSIONS
this study shows that in advanced atherosclerosis, EP4 deficiency did not alter atherosclerotic lesion size, but yielded plaques with exacerbated inflammation and altered lesion composition.
Tang
Eva H C
EH
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB741, Boston, MA 02115, USA.
Shimizu
Koichi
K
Christen
Thomas
T
Rocha
Viviane Z
VZ
Shvartz
Eugenia
E
Tesmenitsky
Yevgenia
Y
Sukhova
Galina
G
Shi
Guo-Ping
GP
Libby
Peter
P
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000235:genetics; D054357:Chemokine CXCL10 / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D017931:DNA Primers; D011973:Receptors, LDL; D058309:Receptors, Prostaglandin E, EP4 Subtype