Lack of EP4 receptors on bone marrow-derived cells enhances inflammation in atherosclerotic lesions

• Published in: Cardiovascular research Vol. 89; no. 1; pp. 234 - 243
• Main Authors: TANG, Eva H. C, SHIMIZU, Koichi, CHRISTEN, Thomas, MOCHA, Viviane Z, SHVARTZ, Eugenia, TESMENITSKY, Yevgenia, SUKHOVA, Galina, SHI, Guo-Ping, LIBBY, Peter
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.2011
• Subjects: Animals; Apoptosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Bone Marrow Transplantation; Cardiology. Vascular system; Chemokine CCL2 - genetics; Chemokine CXCL10 - genetics; DNA Primers - genetics; Female; Inflammation - metabolism; Inflammation - pathology; Male; Medical sciences; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Models, Cardiovascular; Original; Plaque, Atherosclerotic - genetics; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Receptors, LDL - deficiency; Receptors, LDL - genetics; Receptors, Prostaglandin E, EP4 Subtype - deficiency; Receptors, Prostaglandin E, EP4 Subtype - genetics; Receptors, Prostaglandin E, EP4 Subtype - metabolism; Atherogenesis; Cardiovascular disease; Inflammation; Phlebology; Vascular disease; E prostanoid receptor 4; EP4 receptor; Atherosclerosis; Prostanoid; Bone marrow; Circulatory system; Lesion; Cardiology; Cell; Biological receptor
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvq262

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. 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. 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.