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Complement C5a inhibition reduces atherosclerosis in ApoE–/– mice
ABSTRACT The complement C5a receptor, CD88, is present on many of the cells found within human atherosclerotic plaques, but little is known about the role of C5a in atherogenesis. Using real‐time PCR, we determined that ApoE–/– mice fed a normal diet express more aortic CD88 mRNA compared with contr...
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| Published in: | The FASEB journal 2011-07, Vol.25 (7), p.2447-2455 |
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| cites | cdi_FETCH-LOGICAL-c4045-4eb666eccb80dee410b2845d8ba649f5582ff62461ead7d560df8897b8d88bee3 |
| container_end_page | 2455 |
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| container_start_page | 2447 |
| container_title | The FASEB journal |
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| creator | Manthey, Helga D. Thomas, Anita C. Shiels, Ian A. Zernecke, Alma Woodruff, Trent M. Rolfe, Barbara Taylor, Stephen M. |
| description | ABSTRACT
The complement C5a receptor, CD88, is present on many of the cells found within human atherosclerotic plaques, but little is known about the role of C5a in atherogenesis. Using real‐time PCR, we determined that ApoE–/– mice fed a normal diet express more aortic CD88 mRNA compared with controls, and this increase coincides with atherosclerotic lesion development (P< 0.001 for 3‐ vs. 25‐wk‐old animals). Conversely, mRNA expression of the alternative C5a receptor, C5L2, in aortas of ApoE–/– mice, was lower than controls at all time points. Using immunohistochemistry, we confirmed the presence of CD88 on macrophages, smooth muscle cells, and activated endothelial cells in plaques from brachiocephalic arteries. Treatment of ApoE–/– mice with a CD88 antagonist (PMX53; 3 mg/kg s.c. 3×/wk plus 1 mg/kg/d p.o.) for 25 wk reduced lesion size and lipid content in the plaque by ~40% (P |
| doi_str_mv | 10.1096/fj.10-174284 |
| format | article |
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The complement C5a receptor, CD88, is present on many of the cells found within human atherosclerotic plaques, but little is known about the role of C5a in atherogenesis. Using real‐time PCR, we determined that ApoE–/– mice fed a normal diet express more aortic CD88 mRNA compared with controls, and this increase coincides with atherosclerotic lesion development (P< 0.001 for 3‐ vs. 25‐wk‐old animals). Conversely, mRNA expression of the alternative C5a receptor, C5L2, in aortas of ApoE–/– mice, was lower than controls at all time points. Using immunohistochemistry, we confirmed the presence of CD88 on macrophages, smooth muscle cells, and activated endothelial cells in plaques from brachiocephalic arteries. Treatment of ApoE–/– mice with a CD88 antagonist (PMX53; 3 mg/kg s.c. 3×/wk plus 1 mg/kg/d p.o.) for 25 wk reduced lesion size and lipid content in the plaque by ~40% (P<0.05). Our study provides evidence for a proatherogenic role for C5a and identifies the CD88 antagonist PMX53 as a potential antiatherosclerotic drug.—Manthey, H. D., Thomas, A. C., Shiels, I. A., Zernecke, A., Woodruff, T. M., Rolfe, B., Taylor, S. M. Complement C5a inhibition reduces atherosclerosis in ApoE–/– mice. FASEB J. 25, 2447–2455 (2011). www.fasebj.org</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.10-174284</identifier><identifier>PMID: 21490292</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Aorta - drug effects ; Aorta - metabolism ; Aorta - pathology ; Apolipoproteins E - deficiency ; Apolipoproteins E - genetics ; Atherosclerosis - genetics ; Atherosclerosis - metabolism ; Atherosclerosis - prevention & control ; Brachiocephalic Trunk - drug effects ; Brachiocephalic Trunk - metabolism ; Brachiocephalic Trunk - pathology ; C5a receptor ; Cholesterol - blood ; Complement C5a - antagonists & inhibitors ; Complement C5a - metabolism ; Endothelial Cells - metabolism ; Female ; Immunohistochemistry ; Lipids - analysis ; Lipids - blood ; macrophage ; Macrophages - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocytes, Smooth Muscle - metabolism ; Peptides, Cyclic - pharmacology ; PMX53 ; Receptor, Anaphylatoxin C5a - antagonists & inhibitors ; Receptor, Anaphylatoxin C5a - genetics ; Receptor, Anaphylatoxin C5a - metabolism ; Receptors, Chemokine - genetics ; Receptors, Chemokine - metabolism ; Reverse Transcriptase Polymerase Chain Reaction</subject><ispartof>The FASEB journal, 2011-07, Vol.25 (7), p.2447-2455</ispartof><rights>2011 FASEB</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4045-4eb666eccb80dee410b2845d8ba649f5582ff62461ead7d560df8897b8d88bee3</citedby><cites>FETCH-LOGICAL-c4045-4eb666eccb80dee410b2845d8ba649f5582ff62461ead7d560df8897b8d88bee3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21490292$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Manthey, Helga D.</creatorcontrib><creatorcontrib>Thomas, Anita C.</creatorcontrib><creatorcontrib>Shiels, Ian A.</creatorcontrib><creatorcontrib>Zernecke, Alma</creatorcontrib><creatorcontrib>Woodruff, Trent M.</creatorcontrib><creatorcontrib>Rolfe, Barbara</creatorcontrib><creatorcontrib>Taylor, Stephen M.</creatorcontrib><title>Complement C5a inhibition reduces atherosclerosis in ApoE–/– mice</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>ABSTRACT
The complement C5a receptor, CD88, is present on many of the cells found within human atherosclerotic plaques, but little is known about the role of C5a in atherogenesis. Using real‐time PCR, we determined that ApoE–/– mice fed a normal diet express more aortic CD88 mRNA compared with controls, and this increase coincides with atherosclerotic lesion development (P< 0.001 for 3‐ vs. 25‐wk‐old animals). Conversely, mRNA expression of the alternative C5a receptor, C5L2, in aortas of ApoE–/– mice, was lower than controls at all time points. Using immunohistochemistry, we confirmed the presence of CD88 on macrophages, smooth muscle cells, and activated endothelial cells in plaques from brachiocephalic arteries. Treatment of ApoE–/– mice with a CD88 antagonist (PMX53; 3 mg/kg s.c. 3×/wk plus 1 mg/kg/d p.o.) for 25 wk reduced lesion size and lipid content in the plaque by ~40% (P<0.05). Our study provides evidence for a proatherogenic role for C5a and identifies the CD88 antagonist PMX53 as a potential antiatherosclerotic drug.—Manthey, H. D., Thomas, A. C., Shiels, I. A., Zernecke, A., Woodruff, T. M., Rolfe, B., Taylor, S. M. Complement C5a inhibition reduces atherosclerosis in ApoE–/– mice. FASEB J. 25, 2447–2455 (2011). www.fasebj.org</description><subject>Animals</subject><subject>Aorta - drug effects</subject><subject>Aorta - metabolism</subject><subject>Aorta - pathology</subject><subject>Apolipoproteins E - deficiency</subject><subject>Apolipoproteins E - genetics</subject><subject>Atherosclerosis - genetics</subject><subject>Atherosclerosis - metabolism</subject><subject>Atherosclerosis - prevention & control</subject><subject>Brachiocephalic Trunk - drug effects</subject><subject>Brachiocephalic Trunk - metabolism</subject><subject>Brachiocephalic Trunk - pathology</subject><subject>C5a receptor</subject><subject>Cholesterol - blood</subject><subject>Complement C5a - antagonists & inhibitors</subject><subject>Complement C5a - metabolism</subject><subject>Endothelial Cells - metabolism</subject><subject>Female</subject><subject>Immunohistochemistry</subject><subject>Lipids - analysis</subject><subject>Lipids - blood</subject><subject>macrophage</subject><subject>Macrophages - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>PMX53</subject><subject>Receptor, Anaphylatoxin C5a - antagonists & inhibitors</subject><subject>Receptor, Anaphylatoxin C5a - genetics</subject><subject>Receptor, Anaphylatoxin C5a - metabolism</subject><subject>Receptors, Chemokine - genetics</subject><subject>Receptors, Chemokine - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNp9kL1OwzAUhS0EoqWwMaNsLIReO7bjjCVqAQmJAZijOL5RXeWPOBXqxjvwhjwJ7g-MDPeeM3w6OjqEXFK4pZDIabnyGtKYM8WPyJiKCEKpJByTMaiEhVJGakTOnFsBAAUqT8mIUZ4AS9iYzNO27iqssRmCVOSBbZZW28G2TdCjWRfognxYYt-6otp-6zwSzLp2_v35NfUX1LbAc3JS5pXDi4NOyNti_po-hE_P94_p7CksOHARctRSSiwKrcAgcgralxZG6VzypBRCsbKUjEuKuYmNkGBKpZJYK6OURowm5Hqf2_Xt-xrdkNXWFVhVeYPt2mUq5lzJmElP3uzJwpd2PZZZ19s67zcZhWy7W1audna3m8evDsFrXaP5g3-H8kC8Bz5shZt_w7LFyx0DJgBiiET0A4AFehE</recordid><startdate>201107</startdate><enddate>201107</enddate><creator>Manthey, Helga D.</creator><creator>Thomas, Anita C.</creator><creator>Shiels, Ian A.</creator><creator>Zernecke, Alma</creator><creator>Woodruff, Trent M.</creator><creator>Rolfe, Barbara</creator><creator>Taylor, Stephen M.</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201107</creationdate><title>Complement C5a inhibition reduces atherosclerosis in ApoE–/– mice</title><author>Manthey, Helga D. ; Thomas, Anita C. ; Shiels, Ian A. ; Zernecke, Alma ; Woodruff, Trent M. ; Rolfe, Barbara ; Taylor, Stephen M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4045-4eb666eccb80dee410b2845d8ba649f5582ff62461ead7d560df8897b8d88bee3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Aorta - drug effects</topic><topic>Aorta - metabolism</topic><topic>Aorta - pathology</topic><topic>Apolipoproteins E - deficiency</topic><topic>Apolipoproteins E - genetics</topic><topic>Atherosclerosis - genetics</topic><topic>Atherosclerosis - metabolism</topic><topic>Atherosclerosis - prevention & control</topic><topic>Brachiocephalic Trunk - drug effects</topic><topic>Brachiocephalic Trunk - metabolism</topic><topic>Brachiocephalic Trunk - pathology</topic><topic>C5a receptor</topic><topic>Cholesterol - blood</topic><topic>Complement C5a - antagonists & inhibitors</topic><topic>Complement C5a - metabolism</topic><topic>Endothelial Cells - metabolism</topic><topic>Female</topic><topic>Immunohistochemistry</topic><topic>Lipids - analysis</topic><topic>Lipids - blood</topic><topic>macrophage</topic><topic>Macrophages - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>PMX53</topic><topic>Receptor, Anaphylatoxin C5a - antagonists & inhibitors</topic><topic>Receptor, Anaphylatoxin C5a - genetics</topic><topic>Receptor, Anaphylatoxin C5a - metabolism</topic><topic>Receptors, Chemokine - genetics</topic><topic>Receptors, Chemokine - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Manthey, Helga D.</creatorcontrib><creatorcontrib>Thomas, Anita C.</creatorcontrib><creatorcontrib>Shiels, Ian A.</creatorcontrib><creatorcontrib>Zernecke, Alma</creatorcontrib><creatorcontrib>Woodruff, Trent M.</creatorcontrib><creatorcontrib>Rolfe, Barbara</creatorcontrib><creatorcontrib>Taylor, Stephen M.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Manthey, Helga D.</au><au>Thomas, Anita C.</au><au>Shiels, Ian A.</au><au>Zernecke, Alma</au><au>Woodruff, Trent M.</au><au>Rolfe, Barbara</au><au>Taylor, Stephen M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Complement C5a inhibition reduces atherosclerosis in ApoE–/– mice</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2011-07</date><risdate>2011</risdate><volume>25</volume><issue>7</issue><spage>2447</spage><epage>2455</epage><pages>2447-2455</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>ABSTRACT
The complement C5a receptor, CD88, is present on many of the cells found within human atherosclerotic plaques, but little is known about the role of C5a in atherogenesis. Using real‐time PCR, we determined that ApoE–/– mice fed a normal diet express more aortic CD88 mRNA compared with controls, and this increase coincides with atherosclerotic lesion development (P< 0.001 for 3‐ vs. 25‐wk‐old animals). Conversely, mRNA expression of the alternative C5a receptor, C5L2, in aortas of ApoE–/– mice, was lower than controls at all time points. Using immunohistochemistry, we confirmed the presence of CD88 on macrophages, smooth muscle cells, and activated endothelial cells in plaques from brachiocephalic arteries. Treatment of ApoE–/– mice with a CD88 antagonist (PMX53; 3 mg/kg s.c. 3×/wk plus 1 mg/kg/d p.o.) for 25 wk reduced lesion size and lipid content in the plaque by ~40% (P<0.05). Our study provides evidence for a proatherogenic role for C5a and identifies the CD88 antagonist PMX53 as a potential antiatherosclerotic drug.—Manthey, H. D., Thomas, A. C., Shiels, I. A., Zernecke, A., Woodruff, T. M., Rolfe, B., Taylor, S. M. Complement C5a inhibition reduces atherosclerosis in ApoE–/– mice. FASEB J. 25, 2447–2455 (2011). www.fasebj.org</abstract><cop>United States</cop><pmid>21490292</pmid><doi>10.1096/fj.10-174284</doi><tpages>9</tpages></addata></record> |
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| subjects | Animals Aorta - drug effects Aorta - metabolism Aorta - pathology Apolipoproteins E - deficiency Apolipoproteins E - genetics Atherosclerosis - genetics Atherosclerosis - metabolism Atherosclerosis - prevention & control Brachiocephalic Trunk - drug effects Brachiocephalic Trunk - metabolism Brachiocephalic Trunk - pathology C5a receptor Cholesterol - blood Complement C5a - antagonists & inhibitors Complement C5a - metabolism Endothelial Cells - metabolism Female Immunohistochemistry Lipids - analysis Lipids - blood macrophage Macrophages - metabolism Mice Mice, Inbred C57BL Mice, Knockout Myocytes, Smooth Muscle - metabolism Peptides, Cyclic - pharmacology PMX53 Receptor, Anaphylatoxin C5a - antagonists & inhibitors Receptor, Anaphylatoxin C5a - genetics Receptor, Anaphylatoxin C5a - metabolism Receptors, Chemokine - genetics Receptors, Chemokine - metabolism Reverse Transcriptase Polymerase Chain Reaction |
| title | Complement C5a inhibition reduces atherosclerosis in ApoE–/– mice |
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