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Tumor necrosis factor receptor associated factor 6 is not required for atherogenesis in mice and does not associate with atherosclerosis in humans
Tumor necrosis factor receptor-associated factors (TRAFs) are important signaling molecules for a variety of pro-atherogenic cytokines including CD40L, TNF alpha, and IL1beta. Several lines of evidence identified TRAF6 as a pro-inflammatory signaling molecule in vitro and we previously demonstrated...
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Published in: | PloS one 2010-07, Vol.5 (7), p.e11589 |
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description | Tumor necrosis factor receptor-associated factors (TRAFs) are important signaling molecules for a variety of pro-atherogenic cytokines including CD40L, TNF alpha, and IL1beta. Several lines of evidence identified TRAF6 as a pro-inflammatory signaling molecule in vitro and we previously demonstrated overexpression of TRAF6 in human and Murine atherosclerotic plaques. This study investigated the role of TRAF6-deficiency in mice developing atherosclerosis, a chronic inflammatory disease.
Lethally irradiated low density lipoprotein receptor-deficient mice (TRAF6(+/+)/LDLR(-/-)) were reconstituted with TRAF6-deficient fetal liver cells (FLC) and consumed high cholesterol diet for 18 weeks to assess the relevance of TRAF6 in hematopoietic cells for atherogenesis. Additionally, TRAF6(+/-)/LDLR(-/-) mice received TRAF6-deficient FLC to gain insight into the role of TRAF6 deficiency in resident cells. Surprisingly, atherosclerotic lesion size did not differ between the three groups in both aortic roots and abdominal aortas. Similarly, no significant differences in plaque composition could be observed as assessed by immunohistochemistry for macrophages, lipids, smooth muscle cells, T-cells, and collagen. In accord, in a small clinical study TRAF6/GAPDH total blood RNA ratios did not differ between groups of patients with stable coronary heart disease (0.034+/-0.0021, N = 178), acute coronary heart disease (0.029+/-0.0027, N = 70), and those without coronary heart disease (0.032+/-0.0016, N = 77) as assessed by angiography.
Our study demonstrates that TRAF6 is not required for atherogenesis in mice and does not associate with clinical disease in humans. These data suggest that pro- and anti-inflammatory features of TRAF6 signaling outweigh each other in the context of atherosclerosis. |
doi_str_mv | 10.1371/journal.pone.0011589 |
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Lethally irradiated low density lipoprotein receptor-deficient mice (TRAF6(+/+)/LDLR(-/-)) were reconstituted with TRAF6-deficient fetal liver cells (FLC) and consumed high cholesterol diet for 18 weeks to assess the relevance of TRAF6 in hematopoietic cells for atherogenesis. Additionally, TRAF6(+/-)/LDLR(-/-) mice received TRAF6-deficient FLC to gain insight into the role of TRAF6 deficiency in resident cells. Surprisingly, atherosclerotic lesion size did not differ between the three groups in both aortic roots and abdominal aortas. Similarly, no significant differences in plaque composition could be observed as assessed by immunohistochemistry for macrophages, lipids, smooth muscle cells, T-cells, and collagen. In accord, in a small clinical study TRAF6/GAPDH total blood RNA ratios did not differ between groups of patients with stable coronary heart disease (0.034+/-0.0021, N = 178), acute coronary heart disease (0.029+/-0.0027, N = 70), and those without coronary heart disease (0.032+/-0.0016, N = 77) as assessed by angiography.
Our study demonstrates that TRAF6 is not required for atherogenesis in mice and does not associate with clinical disease in humans. These data suggest that pro- and anti-inflammatory features of TRAF6 signaling outweigh each other in the context of atherosclerosis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0011589</identifier><identifier>PMID: 20644648</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Angiography ; Animals ; Aorta ; Aorta, Abdominal - metabolism ; Apolipoproteins ; Arteriosclerosis ; Atherogenesis ; Atherosclerosis ; Atherosclerosis - genetics ; Atherosclerosis - metabolism ; B cells ; Biology ; Bone marrow ; Cardiology ; Cardiovascular diseases ; Cardiovascular Disorders ; Cardiovascular Disorders/Coronary Artery Disease ; Cardiovascular Disorders/Vascular Biology ; CD40L protein ; Cells, Cultured ; Cholesterol ; Cholesterol - adverse effects ; Cholesterol - blood ; Collagen ; Collagen Type I - genetics ; Collagen Type I - metabolism ; Coronary artery disease ; Coronary heart disease ; Cytokines ; Dietary Fats - adverse effects ; Female ; Fetuses ; Flow Cytometry ; Glyceraldehyde-3-phosphate dehydrogenase ; Heart ; Heart diseases ; Hematology ; Hematopoiesis - genetics ; Hematopoiesis - physiology ; Hepatocytes ; High cholesterol diet ; Humans ; Immunohistochemistry ; Inflammation ; Interleukin 1 ; Ligands ; Lipids ; Liver ; Liver Transplantation ; Liver transplants ; Low density lipoprotein receptors ; Lymphocytes T ; Macrophages ; Mice ; Mice, Mutant Strains ; Necrosis ; Plaques ; Polymerase Chain Reaction ; Pregnancy ; Receptor density ; Receptors, LDL - genetics ; Receptors, LDL - physiology ; Residential density ; Ribonucleic acid ; RNA ; Rodents ; Signaling ; Smooth muscle ; T cells ; TNF Receptor-Associated Factor 6 - genetics ; TNF Receptor-Associated Factor 6 - metabolism ; Tumor necrosis factor ; Tumor necrosis factor-TNF ; Tumors ; Weight Gain - drug effects</subject><ispartof>PloS one, 2010-07, Vol.5 (7), p.e11589</ispartof><rights>COPYRIGHT 2010 Public Library of Science</rights><rights>2010 Stachon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Stachon et al. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c723t-eb04ec2a1370ea153095eb703f4fd5206ab9b43bffa4a8fd97cce4a4b247c65b3</citedby><cites>FETCH-LOGICAL-c723t-eb04ec2a1370ea153095eb703f4fd5206ab9b43bffa4a8fd97cce4a4b247c65b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1291896249/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1291896249?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20644648$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Cao, Yihai</contributor><creatorcontrib>Stachon, Peter</creatorcontrib><creatorcontrib>Missiou, Anna</creatorcontrib><creatorcontrib>Walter, Carina</creatorcontrib><creatorcontrib>Varo, Nerea</creatorcontrib><creatorcontrib>Colberg, Christian</creatorcontrib><creatorcontrib>Wolf, Dennis</creatorcontrib><creatorcontrib>Buchner, Maike</creatorcontrib><creatorcontrib>von Zur Mühlen, Constantin</creatorcontrib><creatorcontrib>Zirlik, Katja</creatorcontrib><creatorcontrib>Bode, Christoph</creatorcontrib><creatorcontrib>Zirlik, Andreas</creatorcontrib><title>Tumor necrosis factor receptor associated factor 6 is not required for atherogenesis in mice and does not associate with atherosclerosis in humans</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Tumor necrosis factor receptor-associated factors (TRAFs) are important signaling molecules for a variety of pro-atherogenic cytokines including CD40L, TNF alpha, and IL1beta. Several lines of evidence identified TRAF6 as a pro-inflammatory signaling molecule in vitro and we previously demonstrated overexpression of TRAF6 in human and Murine atherosclerotic plaques. This study investigated the role of TRAF6-deficiency in mice developing atherosclerosis, a chronic inflammatory disease.
Lethally irradiated low density lipoprotein receptor-deficient mice (TRAF6(+/+)/LDLR(-/-)) were reconstituted with TRAF6-deficient fetal liver cells (FLC) and consumed high cholesterol diet for 18 weeks to assess the relevance of TRAF6 in hematopoietic cells for atherogenesis. Additionally, TRAF6(+/-)/LDLR(-/-) mice received TRAF6-deficient FLC to gain insight into the role of TRAF6 deficiency in resident cells. Surprisingly, atherosclerotic lesion size did not differ between the three groups in both aortic roots and abdominal aortas. Similarly, no significant differences in plaque composition could be observed as assessed by immunohistochemistry for macrophages, lipids, smooth muscle cells, T-cells, and collagen. In accord, in a small clinical study TRAF6/GAPDH total blood RNA ratios did not differ between groups of patients with stable coronary heart disease (0.034+/-0.0021, N = 178), acute coronary heart disease (0.029+/-0.0027, N = 70), and those without coronary heart disease (0.032+/-0.0016, N = 77) as assessed by angiography.
Our study demonstrates that TRAF6 is not required for atherogenesis in mice and does not associate with clinical disease in humans. These data suggest that pro- and anti-inflammatory features of TRAF6 signaling outweigh each other in the context of atherosclerosis.</description><subject>Angiography</subject><subject>Animals</subject><subject>Aorta</subject><subject>Aorta, Abdominal - metabolism</subject><subject>Apolipoproteins</subject><subject>Arteriosclerosis</subject><subject>Atherogenesis</subject><subject>Atherosclerosis</subject><subject>Atherosclerosis - genetics</subject><subject>Atherosclerosis - metabolism</subject><subject>B cells</subject><subject>Biology</subject><subject>Bone marrow</subject><subject>Cardiology</subject><subject>Cardiovascular diseases</subject><subject>Cardiovascular Disorders</subject><subject>Cardiovascular Disorders/Coronary Artery Disease</subject><subject>Cardiovascular Disorders/Vascular Biology</subject><subject>CD40L protein</subject><subject>Cells, Cultured</subject><subject>Cholesterol</subject><subject>Cholesterol - adverse effects</subject><subject>Cholesterol - blood</subject><subject>Collagen</subject><subject>Collagen Type I - genetics</subject><subject>Collagen Type I - metabolism</subject><subject>Coronary artery disease</subject><subject>Coronary heart disease</subject><subject>Cytokines</subject><subject>Dietary Fats - adverse effects</subject><subject>Female</subject><subject>Fetuses</subject><subject>Flow Cytometry</subject><subject>Glyceraldehyde-3-phosphate dehydrogenase</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Hematology</subject><subject>Hematopoiesis - genetics</subject><subject>Hematopoiesis - physiology</subject><subject>Hepatocytes</subject><subject>High cholesterol diet</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Inflammation</subject><subject>Interleukin 1</subject><subject>Ligands</subject><subject>Lipids</subject><subject>Liver</subject><subject>Liver Transplantation</subject><subject>Liver transplants</subject><subject>Low density lipoprotein receptors</subject><subject>Lymphocytes T</subject><subject>Macrophages</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Necrosis</subject><subject>Plaques</subject><subject>Polymerase Chain Reaction</subject><subject>Pregnancy</subject><subject>Receptor density</subject><subject>Receptors, LDL - genetics</subject><subject>Receptors, LDL - physiology</subject><subject>Residential density</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Rodents</subject><subject>Signaling</subject><subject>Smooth muscle</subject><subject>T cells</subject><subject>TNF Receptor-Associated Factor 6 - genetics</subject><subject>TNF Receptor-Associated Factor 6 - metabolism</subject><subject>Tumor necrosis factor</subject><subject>Tumor necrosis factor-TNF</subject><subject>Tumors</subject><subject>Weight Gain - drug effects</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tu1DAQhiMEoqXwBggiIYG42MWJD0luKlUVh5UqVYLCrTVxJhtXWXtrOxxegyfGYbOrDeoFykUcz_f_kxl7kuR5RpYZLbJ3t3ZwBvrl1hpcEpJlvKweJKdZRfOFyAl9eLQ-SZ54f0sIp6UQj5OTnAjGBCtPk983w8a61KBy1muftqBC_HaocDsuwHurNARs9iGRRszYEJm7QbsxMHKhQ2fXaHB00SbdaIUpmCZtLO74g1X6Q4duUnjV4y5z1HTDBox_mjxqoff4bHqfJV8_vL-5_LS4uv64ury4Wqgip2GBNWGocojNIAgZp6TiWBeEtqxteKwQ6qpmtG5bYFC2TVUohQxYnbNCCV7Ts-TlznfbWy-ndnqZ5VVWViJnVSRWO6KxcCu3Tm_A_ZIWtPy7Yd1aggs6liAFCJYXDZSk4YxURU0okLwRyCshymr0Op-yDfUGG4UmOOhnpvOI0Z1c2-8yrwijZRkN3kwGzt4N6IPcaK-w78GgHbwsOOOcs5JH8tU_5P3FTdQa4v9r09qYVo2e8oIVY0ZWsEgt76Hi02A84Xj1Wh33Z4K3M0FkAv4Maxi8l6svn_-fvf42Z18fsR1CHzpv-yFoa_wcZDtwvNHeYXvocUbkODn7bshxcuQ0OVH24vh8DqL9qNA_OfAWbA</recordid><startdate>20100714</startdate><enddate>20100714</enddate><creator>Stachon, Peter</creator><creator>Missiou, Anna</creator><creator>Walter, Carina</creator><creator>Varo, Nerea</creator><creator>Colberg, Christian</creator><creator>Wolf, Dennis</creator><creator>Buchner, Maike</creator><creator>von Zur Mühlen, Constantin</creator><creator>Zirlik, Katja</creator><creator>Bode, Christoph</creator><creator>Zirlik, Andreas</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20100714</creationdate><title>Tumor necrosis factor receptor associated factor 6 is not required for atherogenesis in mice and does not associate with atherosclerosis in humans</title><author>Stachon, Peter ; Missiou, Anna ; Walter, Carina ; Varo, Nerea ; Colberg, Christian ; Wolf, Dennis ; Buchner, Maike ; von Zur Mühlen, Constantin ; Zirlik, Katja ; Bode, Christoph ; Zirlik, Andreas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c723t-eb04ec2a1370ea153095eb703f4fd5206ab9b43bffa4a8fd97cce4a4b247c65b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Angiography</topic><topic>Animals</topic><topic>Aorta</topic><topic>Aorta, Abdominal - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials science collection</collection><collection>Publicly Available Content (ProQuest)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Stachon, Peter</au><au>Missiou, Anna</au><au>Walter, Carina</au><au>Varo, Nerea</au><au>Colberg, Christian</au><au>Wolf, Dennis</au><au>Buchner, Maike</au><au>von Zur Mühlen, Constantin</au><au>Zirlik, Katja</au><au>Bode, Christoph</au><au>Zirlik, Andreas</au><au>Cao, Yihai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumor necrosis factor receptor associated factor 6 is not required for atherogenesis in mice and does not associate with atherosclerosis in humans</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2010-07-14</date><risdate>2010</risdate><volume>5</volume><issue>7</issue><spage>e11589</spage><pages>e11589-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Tumor necrosis factor receptor-associated factors (TRAFs) are important signaling molecules for a variety of pro-atherogenic cytokines including CD40L, TNF alpha, and IL1beta. Several lines of evidence identified TRAF6 as a pro-inflammatory signaling molecule in vitro and we previously demonstrated overexpression of TRAF6 in human and Murine atherosclerotic plaques. This study investigated the role of TRAF6-deficiency in mice developing atherosclerosis, a chronic inflammatory disease.
Lethally irradiated low density lipoprotein receptor-deficient mice (TRAF6(+/+)/LDLR(-/-)) were reconstituted with TRAF6-deficient fetal liver cells (FLC) and consumed high cholesterol diet for 18 weeks to assess the relevance of TRAF6 in hematopoietic cells for atherogenesis. Additionally, TRAF6(+/-)/LDLR(-/-) mice received TRAF6-deficient FLC to gain insight into the role of TRAF6 deficiency in resident cells. Surprisingly, atherosclerotic lesion size did not differ between the three groups in both aortic roots and abdominal aortas. Similarly, no significant differences in plaque composition could be observed as assessed by immunohistochemistry for macrophages, lipids, smooth muscle cells, T-cells, and collagen. In accord, in a small clinical study TRAF6/GAPDH total blood RNA ratios did not differ between groups of patients with stable coronary heart disease (0.034+/-0.0021, N = 178), acute coronary heart disease (0.029+/-0.0027, N = 70), and those without coronary heart disease (0.032+/-0.0016, N = 77) as assessed by angiography.
Our study demonstrates that TRAF6 is not required for atherogenesis in mice and does not associate with clinical disease in humans. These data suggest that pro- and anti-inflammatory features of TRAF6 signaling outweigh each other in the context of atherosclerosis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>20644648</pmid><doi>10.1371/journal.pone.0011589</doi><tpages>e11589</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2010-07, Vol.5 (7), p.e11589 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1291896249 |
source | Publicly Available Content (ProQuest); PubMed Central |
subjects | Angiography Animals Aorta Aorta, Abdominal - metabolism Apolipoproteins Arteriosclerosis Atherogenesis Atherosclerosis Atherosclerosis - genetics Atherosclerosis - metabolism B cells Biology Bone marrow Cardiology Cardiovascular diseases Cardiovascular Disorders Cardiovascular Disorders/Coronary Artery Disease Cardiovascular Disorders/Vascular Biology CD40L protein Cells, Cultured Cholesterol Cholesterol - adverse effects Cholesterol - blood Collagen Collagen Type I - genetics Collagen Type I - metabolism Coronary artery disease Coronary heart disease Cytokines Dietary Fats - adverse effects Female Fetuses Flow Cytometry Glyceraldehyde-3-phosphate dehydrogenase Heart Heart diseases Hematology Hematopoiesis - genetics Hematopoiesis - physiology Hepatocytes High cholesterol diet Humans Immunohistochemistry Inflammation Interleukin 1 Ligands Lipids Liver Liver Transplantation Liver transplants Low density lipoprotein receptors Lymphocytes T Macrophages Mice Mice, Mutant Strains Necrosis Plaques Polymerase Chain Reaction Pregnancy Receptor density Receptors, LDL - genetics Receptors, LDL - physiology Residential density Ribonucleic acid RNA Rodents Signaling Smooth muscle T cells TNF Receptor-Associated Factor 6 - genetics TNF Receptor-Associated Factor 6 - metabolism Tumor necrosis factor Tumor necrosis factor-TNF Tumors Weight Gain - drug effects |
title | Tumor necrosis factor receptor associated factor 6 is not required for atherogenesis in mice and does not associate with atherosclerosis in humans |
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