AIM: 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. METHODS AND 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. CONCLUSION: 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.
AIM: 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. METHODS AND 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. CONCLUSION: 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.
Authors: Sandhya Sanghi; Eric J MacLaughlin; Coty W Jewell; Sheldon Chaffer; Peter J Naus; Linley E Watson; David E Dostal Journal: Cardiovasc Hematol Disord Drug Targets Date: 2006-06
Authors: Vladimir R Babaev; Joshua D Chew; Lei Ding; Sarah Davis; Matthew D Breyer; Richard M Breyer; John A Oates; Sergio Fazio; Macrae F Linton Journal: Cell Metab Date: 2008-12 Impact factor: 27.287
Authors: Jiusong Sun; Galina K Sukhova; Min Yang; Paul J Wolters; Lindsey A MacFarlane; Peter Libby; Chongxiu Sun; Yadong Zhang; Jian Liu; Terri L Ennis; Rebecca Knispel; Wanfen Xiong; Robert W Thompson; B Timothy Baxter; Guo-Ping Shi Journal: J Clin Invest Date: 2007-11 Impact factor: 14.808
Authors: Constantin von zur Muhlen; Eric Schiffer; Christine Sackmann; Petra Zürbig; Irene Neudorfer; Andreas Zirlik; Nay Htun; Alexander Iphöfer; Lothar Jänsch; Harald Mischak; Christoph Bode; Yung C Chen; Karlheinz Peter Journal: Mol Cell Proteomics Date: 2012-02-27 Impact factor: 5.911
Authors: Eva H C Tang; Yin Cai; Chi Kin Wong; Viviane Z Rocha; Galina K Sukhova; Koichi Shimizu; Ge Xuan; Paul M Vanhoutte; Peter Libby; Aimin Xu Journal: J Lipid Res Date: 2014-12-15 Impact factor: 5.922