Identification of 5-Lipoxygenase as a Major Gene Contributing to Atherosclerosis Susceptibility in Mice
We previously reported the identification of a locus on mouse chromosome 6 that confers almost total resistance to atherogenesis, even on a hypercholesterolemic (LDL receptor–null) background. 5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene synthesis and was among the chromosome 6 l...
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| Veröffentlicht in: | Circulation research 2002-07, Vol.91 (2), p.120-126 |
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| creator | Mehrabian, Margarete Allayee, Hooman Wong, Jack Shih, Weibin Wang, Xu-Ping Shaposhnik, Zory Funk, Colin D Lusis, Aldons J |
| description | We previously reported the identification of a locus on mouse chromosome 6 that confers almost total resistance to atherogenesis, even on a hypercholesterolemic (LDL receptor–null) background. 5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene synthesis and was among the chromosome 6 locus candidate genes that we examined. The levels of 5-LO mRNA were reduced about 5-fold in a congenic strain, designated CON6, containing the resistant chromosome 6 region derived from the CAST/Ei strain (CAST), as compared with the background C57BL/6J (B6) strain. 5-LO protein levels were similarly reduced in the CON6 mice. Sequencing of the 5-LO cDNA revealed several differences between CON6 and the B6 strain. To test the whether 5-LO is responsible for the resistant phenotype, we bred a 5-LO knockout allele onto an LDL receptor–null (LDLR) background. On this background, the mice bred poorly and only heterozygous 5-LO knockout mice were obtained. These mice showed a dramatic decrease (>26-fold;P |
| doi_str_mv | 10.1161/01.res.0000028008.99774.7f |
| format | Article |
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The levels of 5-LO mRNA were reduced about 5-fold in a congenic strain, designated CON6, containing the resistant chromosome 6 region derived from the CAST/Ei strain (CAST), as compared with the background C57BL/6J (B6) strain. 5-LO protein levels were similarly reduced in the CON6 mice. Sequencing of the 5-LO cDNA revealed several differences between CON6 and the B6 strain. To test the whether 5-LO is responsible for the resistant phenotype, we bred a 5-LO knockout allele onto an LDL receptor–null (LDLR) background. On this background, the mice bred poorly and only heterozygous 5-LO knockout mice were obtained. These mice showed a dramatic decrease (>26-fold;P <0.0005) in aortic lesion development, similar to the CON6 mice. Immunohistochemistry revealed that 5-LO was abundantly expressed in atherosclerotic lesions of apoE and LDLR deficient mice, appearing to colocalize with a subset of macrophages but not with all macrophage-staining regions. When bone marrow from 5-LO mice was transplanted into LDLR, there was a significant reduction in atherogenesis, suggesting that macrophage 5-LO is responsible, at least in part, for the effect on atherosclerosis. These results indicate that 5-LO contributes importantly to the atherogenic process and they provide strong presumptive evidence that reduced 5-LO expression is partly responsible for the resistance to atherosclerosis in CON6 mice.</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/01.res.0000028008.99774.7f</identifier><identifier>PMID: 12142344</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Alleles ; Amino Acid Substitution ; Animals ; Arachidonate 5-Lipoxygenase - genetics ; Arachidonate 5-Lipoxygenase - physiology ; Arteriosclerosis - enzymology ; Arteriosclerosis - genetics ; Arteriosclerosis - pathology ; Atherosclerosis (general aspects, experimental research) ; Biological and medical sciences ; Blood and lymphatic vessels ; Bone Marrow Transplantation ; Cardiology. Vascular system ; Genetic Predisposition to Disease ; Insulin - blood ; Macrophages - enzymology ; Medical sciences ; Mice ; Mice, Congenic ; Mice, Inbred C57BL ; Mice, Knockout ; Receptors, LDL - genetics ; RNA, Messenger - biosynthesis</subject><ispartof>Circulation research, 2002-07, Vol.91 (2), p.120-126</ispartof><rights>2002 American Heart Association, Inc.</rights><rights>2002 INIST-CNRS</rights><rights>Copyright American Heart Association, Inc. Jul 26, 2002</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6288-5802fa22ab6eadf78bc37795f5e7fe7570bc99b28806938d45dfa4c50a99f6e03</citedby><cites>FETCH-LOGICAL-c6288-5802fa22ab6eadf78bc37795f5e7fe7570bc99b28806938d45dfa4c50a99f6e03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3685,27923,27924</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13831734$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12142344$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mehrabian, Margarete</creatorcontrib><creatorcontrib>Allayee, Hooman</creatorcontrib><creatorcontrib>Wong, Jack</creatorcontrib><creatorcontrib>Shih, Weibin</creatorcontrib><creatorcontrib>Wang, Xu-Ping</creatorcontrib><creatorcontrib>Shaposhnik, Zory</creatorcontrib><creatorcontrib>Funk, Colin D</creatorcontrib><creatorcontrib>Lusis, Aldons J</creatorcontrib><title>Identification of 5-Lipoxygenase as a Major Gene Contributing to Atherosclerosis Susceptibility in Mice</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>We previously reported the identification of a locus on mouse chromosome 6 that confers almost total resistance to atherogenesis, even on a hypercholesterolemic (LDL receptor–null) background. 5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene synthesis and was among the chromosome 6 locus candidate genes that we examined. The levels of 5-LO mRNA were reduced about 5-fold in a congenic strain, designated CON6, containing the resistant chromosome 6 region derived from the CAST/Ei strain (CAST), as compared with the background C57BL/6J (B6) strain. 5-LO protein levels were similarly reduced in the CON6 mice. Sequencing of the 5-LO cDNA revealed several differences between CON6 and the B6 strain. To test the whether 5-LO is responsible for the resistant phenotype, we bred a 5-LO knockout allele onto an LDL receptor–null (LDLR) background. On this background, the mice bred poorly and only heterozygous 5-LO knockout mice were obtained. These mice showed a dramatic decrease (>26-fold;P <0.0005) in aortic lesion development, similar to the CON6 mice. Immunohistochemistry revealed that 5-LO was abundantly expressed in atherosclerotic lesions of apoE and LDLR deficient mice, appearing to colocalize with a subset of macrophages but not with all macrophage-staining regions. When bone marrow from 5-LO mice was transplanted into LDLR, there was a significant reduction in atherogenesis, suggesting that macrophage 5-LO is responsible, at least in part, for the effect on atherosclerosis. These results indicate that 5-LO contributes importantly to the atherogenic process and they provide strong presumptive evidence that reduced 5-LO expression is partly responsible for the resistance to atherosclerosis in CON6 mice.</description><subject>Alleles</subject><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Arachidonate 5-Lipoxygenase - genetics</subject><subject>Arachidonate 5-Lipoxygenase - physiology</subject><subject>Arteriosclerosis - enzymology</subject><subject>Arteriosclerosis - genetics</subject><subject>Arteriosclerosis - pathology</subject><subject>Atherosclerosis (general aspects, experimental research)</subject><subject>Biological and medical sciences</subject><subject>Blood and lymphatic vessels</subject><subject>Bone Marrow Transplantation</subject><subject>Cardiology. Vascular system</subject><subject>Genetic Predisposition to Disease</subject><subject>Insulin - blood</subject><subject>Macrophages - enzymology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Congenic</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Receptors, LDL - genetics</subject><subject>RNA, Messenger - biosynthesis</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkd1qGzEQhZfS0LhpX6GIQHu3G_2upN4Fk6QBh0LTXgutPLLlrleupCX123cdGwydCw2Mvpk50qmqa4IbQlpyg0mTIDf4EFRhrBqtpeSN9G-qGRGU11xI8raaTfe6lozhy-p9zhuMCWdUv6suCSWcMs5n1epxCUMJPjhbQhxQ9EjUi7CLf_crGGwGZDOy6MluYkIPMACax6Gk0I0lDCtUIrota0gxu_5whoyex-xgV0IX-lD2KAzoKTj4UF1422f4eMpX1a_7u5_zb_Xi-8Pj_HZRu5YqVQuFqbeU2q4Fu_RSdY5JqYUXID1IIXHntO4mFLeaqSUXS2-5E9hq7VvA7Kr6cpy7S_HPCLmYbZj09L0dII7ZSKIFU0JO4PV_4CaOaZi0GUoop1jpdoK-HiE3vS0n8GaXwtamvSHYHLwwmJgfd8_m7IV59cLI-6n502nD2G1heW49ff4EfD4BNjvb-2QHF_KZY4oRyQ4cP3IvsS-Q8u9-fIFk1mD7sn5dzTChNZ0UYElbXB9Kiv0Dpoqigg</recordid><startdate>20020726</startdate><enddate>20020726</enddate><creator>Mehrabian, Margarete</creator><creator>Allayee, Hooman</creator><creator>Wong, Jack</creator><creator>Shih, Weibin</creator><creator>Wang, Xu-Ping</creator><creator>Shaposhnik, Zory</creator><creator>Funk, Colin D</creator><creator>Lusis, Aldons J</creator><general>American Heart Association, Inc</general><general>Lippincott</general><general>Lippincott Williams & Wilkins Ovid Technologies</general><scope>IQODW</scope><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>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>20020726</creationdate><title>Identification of 5-Lipoxygenase as a Major Gene Contributing to Atherosclerosis Susceptibility in Mice</title><author>Mehrabian, Margarete ; Allayee, Hooman ; Wong, Jack ; Shih, Weibin ; Wang, Xu-Ping ; Shaposhnik, Zory ; Funk, Colin D ; Lusis, Aldons J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6288-5802fa22ab6eadf78bc37795f5e7fe7570bc99b28806938d45dfa4c50a99f6e03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Alleles</topic><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Arachidonate 5-Lipoxygenase - genetics</topic><topic>Arachidonate 5-Lipoxygenase - physiology</topic><topic>Arteriosclerosis - enzymology</topic><topic>Arteriosclerosis - genetics</topic><topic>Arteriosclerosis - pathology</topic><topic>Atherosclerosis (general aspects, experimental research)</topic><topic>Biological and medical sciences</topic><topic>Blood and lymphatic vessels</topic><topic>Bone Marrow Transplantation</topic><topic>Cardiology. Vascular system</topic><topic>Genetic Predisposition to Disease</topic><topic>Insulin - blood</topic><topic>Macrophages - enzymology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Congenic</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Receptors, LDL - genetics</topic><topic>RNA, Messenger - biosynthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mehrabian, Margarete</creatorcontrib><creatorcontrib>Allayee, Hooman</creatorcontrib><creatorcontrib>Wong, Jack</creatorcontrib><creatorcontrib>Shih, Weibin</creatorcontrib><creatorcontrib>Wang, Xu-Ping</creatorcontrib><creatorcontrib>Shaposhnik, Zory</creatorcontrib><creatorcontrib>Funk, Colin D</creatorcontrib><creatorcontrib>Lusis, Aldons J</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mehrabian, Margarete</au><au>Allayee, Hooman</au><au>Wong, Jack</au><au>Shih, Weibin</au><au>Wang, Xu-Ping</au><au>Shaposhnik, Zory</au><au>Funk, Colin D</au><au>Lusis, Aldons J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of 5-Lipoxygenase as a Major Gene Contributing to Atherosclerosis Susceptibility in Mice</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>2002-07-26</date><risdate>2002</risdate><volume>91</volume><issue>2</issue><spage>120</spage><epage>126</epage><pages>120-126</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><abstract>We previously reported the identification of a locus on mouse chromosome 6 that confers almost total resistance to atherogenesis, even on a hypercholesterolemic (LDL receptor–null) background. 5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene synthesis and was among the chromosome 6 locus candidate genes that we examined. The levels of 5-LO mRNA were reduced about 5-fold in a congenic strain, designated CON6, containing the resistant chromosome 6 region derived from the CAST/Ei strain (CAST), as compared with the background C57BL/6J (B6) strain. 5-LO protein levels were similarly reduced in the CON6 mice. Sequencing of the 5-LO cDNA revealed several differences between CON6 and the B6 strain. To test the whether 5-LO is responsible for the resistant phenotype, we bred a 5-LO knockout allele onto an LDL receptor–null (LDLR) background. On this background, the mice bred poorly and only heterozygous 5-LO knockout mice were obtained. These mice showed a dramatic decrease (>26-fold;P <0.0005) in aortic lesion development, similar to the CON6 mice. Immunohistochemistry revealed that 5-LO was abundantly expressed in atherosclerotic lesions of apoE and LDLR deficient mice, appearing to colocalize with a subset of macrophages but not with all macrophage-staining regions. When bone marrow from 5-LO mice was transplanted into LDLR, there was a significant reduction in atherogenesis, suggesting that macrophage 5-LO is responsible, at least in part, for the effect on atherosclerosis. These results indicate that 5-LO contributes importantly to the atherogenic process and they provide strong presumptive evidence that reduced 5-LO expression is partly responsible for the resistance to atherosclerosis in CON6 mice.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>12142344</pmid><doi>10.1161/01.res.0000028008.99774.7f</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alleles Amino Acid Substitution Animals Arachidonate 5-Lipoxygenase - genetics Arachidonate 5-Lipoxygenase - physiology Arteriosclerosis - enzymology Arteriosclerosis - genetics Arteriosclerosis - pathology Atherosclerosis (general aspects, experimental research) Biological and medical sciences Blood and lymphatic vessels Bone Marrow Transplantation Cardiology. Vascular system Genetic Predisposition to Disease Insulin - blood Macrophages - enzymology Medical sciences Mice Mice, Congenic Mice, Inbred C57BL Mice, Knockout Receptors, LDL - genetics RNA, Messenger - biosynthesis |
| title | Identification of 5-Lipoxygenase as a Major Gene Contributing to Atherosclerosis Susceptibility in Mice |
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