The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE3Leiden.CETP mice
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density li...
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| Veröffentlicht in: | European heart journal 2017-08, Vol.38 (32), p.2499-2507 |
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| container_title | European heart journal |
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| creator | Landlinger, Christine Pouwer, Marianne G Juno, Claudia van der Hoorn, José W A Pieterman, Elsbet J Jukema, J Wouter Staffler, Guenther Princen, Hans M G Galabova, Gergana |
| description | Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher risk of atherosclerosis. In this study, the AT04A anti-PCSK9 vaccine was evaluated for its therapeutic potential in ameliorating or even preventing coronary heart disease in the atherogenic APOE*3Leiden.CETP mouse model.
Control and AT04A vaccine-treated mice were fed western-type diet for 18 weeks. Antibody titres, plasma lipids, and inflammatory markers were monitored by ELISA, FPLC, and multiplexed immunoassay, respectively. The progression of atherosclerosis was evaluated by histological analysis of serial cross-sections from the aortic sinus. The AT04A vaccine induced high and persistent antibody levels against PCSK9, causing a significant reduction in plasma total cholesterol (-53%, P |
| doi_str_mv | 10.1093/eurheartj/ehx260 |
| format | Article |
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Control and AT04A vaccine-treated mice were fed western-type diet for 18 weeks. Antibody titres, plasma lipids, and inflammatory markers were monitored by ELISA, FPLC, and multiplexed immunoassay, respectively. The progression of atherosclerosis was evaluated by histological analysis of serial cross-sections from the aortic sinus. The AT04A vaccine induced high and persistent antibody levels against PCSK9, causing a significant reduction in plasma total cholesterol (-53%, P < 0.001) and LDLc compared with controls. Plasma inflammatory markers such as serum amyloid A (SAA), macrophage inflammatory protein-1β (MIP-1β/CCL4), macrophage-derived chemokine (MDC/CCL22), cytokine stem cell factor (SCF), and vascular endothelial growth factor A (VEGF-A) were significantly diminished in AT04A-treated mice. As a consequence, treatment with the AT04A vaccine resulted in a decrease in atherosclerotic lesion area (-64%, P = 0.004) and aortic inflammation as well as in more lesion-free aortic segments (+119%, P = 0.026), compared with control.
AT04A vaccine induces an effective immune response against PCSK9 in APOE*3Leiden.CETP mice, leading to a significant reduction of plasma lipids, systemic and vascular inflammation, and atherosclerotic lesions in the aorta.</description><identifier>ISSN: 0195-668X</identifier><identifier>EISSN: 1522-9645</identifier><identifier>DOI: 10.1093/eurheartj/ehx260</identifier><identifier>PMID: 28637178</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject><![CDATA[Animals ; Antibodies - metabolism ; Aortic Diseases - prevention & control ; Apolipoprotein E3 - deficiency ; Atherosclerosis - prevention & control ; Basic Science ; Biomarkers - metabolism ; Cholesterol, HDL - metabolism ; Coronary Disease - prevention & control ; Disease Models, Animal ; Editor's Choice ; Female ; Hypercholesterolemia - immunology ; Hypercholesterolemia - prevention & control ; Intercellular Adhesion Molecule-1 - metabolism ; Mice, Transgenic ; NLR Family, Pyrin Domain-Containing 3 Protein - immunology ; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism ; PCSK9 Inhibitors ; Plaque, Atherosclerotic - prevention & control ; Proprotein Convertase 9 - immunology ; Vaccines, Subunit - administration & dosage ; Vaccines, Subunit - immunology ; Vasculitis - immunology ; Vasculitis - prevention & control]]></subject><ispartof>European heart journal, 2017-08, Vol.38 (32), p.2499-2507</ispartof><rights>The Author 2017. Published on behalf of the European Society of Cardiology.</rights><rights>The Author 2017. Published on behalf of the European Society of Cardiology. 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c392t-4ece367f10f9e0096908e75dcd9e646af19ed900f2bfe689952b1c29d47d54ef3</citedby><cites>FETCH-LOGICAL-c392t-4ece367f10f9e0096908e75dcd9e646af19ed900f2bfe689952b1c29d47d54ef3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28637178$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Landlinger, Christine</creatorcontrib><creatorcontrib>Pouwer, Marianne G</creatorcontrib><creatorcontrib>Juno, Claudia</creatorcontrib><creatorcontrib>van der Hoorn, José W A</creatorcontrib><creatorcontrib>Pieterman, Elsbet J</creatorcontrib><creatorcontrib>Jukema, J Wouter</creatorcontrib><creatorcontrib>Staffler, Guenther</creatorcontrib><creatorcontrib>Princen, Hans M G</creatorcontrib><creatorcontrib>Galabova, Gergana</creatorcontrib><title>The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE3Leiden.CETP mice</title><title>European heart journal</title><addtitle>Eur Heart J</addtitle><description>Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher risk of atherosclerosis. In this study, the AT04A anti-PCSK9 vaccine was evaluated for its therapeutic potential in ameliorating or even preventing coronary heart disease in the atherogenic APOE*3Leiden.CETP mouse model.
Control and AT04A vaccine-treated mice were fed western-type diet for 18 weeks. Antibody titres, plasma lipids, and inflammatory markers were monitored by ELISA, FPLC, and multiplexed immunoassay, respectively. The progression of atherosclerosis was evaluated by histological analysis of serial cross-sections from the aortic sinus. The AT04A vaccine induced high and persistent antibody levels against PCSK9, causing a significant reduction in plasma total cholesterol (-53%, P < 0.001) and LDLc compared with controls. Plasma inflammatory markers such as serum amyloid A (SAA), macrophage inflammatory protein-1β (MIP-1β/CCL4), macrophage-derived chemokine (MDC/CCL22), cytokine stem cell factor (SCF), and vascular endothelial growth factor A (VEGF-A) were significantly diminished in AT04A-treated mice. As a consequence, treatment with the AT04A vaccine resulted in a decrease in atherosclerotic lesion area (-64%, P = 0.004) and aortic inflammation as well as in more lesion-free aortic segments (+119%, P = 0.026), compared with control.
AT04A vaccine induces an effective immune response against PCSK9 in APOE*3Leiden.CETP mice, leading to a significant reduction of plasma lipids, systemic and vascular inflammation, and atherosclerotic lesions in the aorta.</description><subject>Animals</subject><subject>Antibodies - metabolism</subject><subject>Aortic Diseases - prevention & control</subject><subject>Apolipoprotein E3 - deficiency</subject><subject>Atherosclerosis - prevention & control</subject><subject>Basic Science</subject><subject>Biomarkers - metabolism</subject><subject>Cholesterol, HDL - metabolism</subject><subject>Coronary Disease - prevention & control</subject><subject>Disease Models, Animal</subject><subject>Editor's Choice</subject><subject>Female</subject><subject>Hypercholesterolemia - immunology</subject><subject>Hypercholesterolemia - prevention & control</subject><subject>Intercellular Adhesion Molecule-1 - metabolism</subject><subject>Mice, Transgenic</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein - immunology</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein - metabolism</subject><subject>PCSK9 Inhibitors</subject><subject>Plaque, Atherosclerotic - prevention & control</subject><subject>Proprotein Convertase 9 - immunology</subject><subject>Vaccines, Subunit - administration & dosage</subject><subject>Vaccines, Subunit - immunology</subject><subject>Vasculitis - immunology</subject><subject>Vasculitis - prevention & control</subject><issn>0195-668X</issn><issn>1522-9645</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUtvGyEUhVHVqnHT7ruqWHaRiWEeDGwqWZb7kCwlC1fqDmG4kyFlwAXGSv5Qf2eJnFqthC6Lc-65cD-E3lNyTYloljDHEVTM90sYH2pGXqAF7eq6EqztXqIFoaKrGOM_LtCblO4JIZxR9hpd1Jw1Pe35Av3ejYBXO9Ku8FFpbT1gdaesTxkfYigng_VYB3-EmFUCnOZ9ts4m65c_4aFo-fEAWOAIZtaQcA5ZOazH4CBliMFdleCkZ6citn5wappUtsFfYeUNVnksnqTdU7WpOPDq9mbTbMEa8Nfrze4WT1bDW_RqUC7Bu-f7En3_vNmtv1bbmy_f1qttpRtR56oFDQ3rB0oGAYQIJgiHvjPaCGAtUwMVYAQhQ70fgHEhunpPdS1M25uuhaG5RJ9OuYd5P4HR4HNUTh6inVR8lEFZ-b_i7SjvwlF2vOl7wkvAx-eAGH7NZQVyskmDc8pDmJOkghZOnNSsWMnJqsvfU4ThPIYS-YRXnvHKE97S8uHf550b_vJs_gBhSqmA</recordid><startdate>20170821</startdate><enddate>20170821</enddate><creator>Landlinger, Christine</creator><creator>Pouwer, Marianne G</creator><creator>Juno, Claudia</creator><creator>van der Hoorn, José W A</creator><creator>Pieterman, Elsbet J</creator><creator>Jukema, J Wouter</creator><creator>Staffler, Guenther</creator><creator>Princen, Hans M G</creator><creator>Galabova, Gergana</creator><general>Oxford University Press</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170821</creationdate><title>The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE3Leiden.CETP mice</title><author>Landlinger, Christine ; Pouwer, Marianne G ; Juno, Claudia ; van der Hoorn, José W A ; Pieterman, Elsbet J ; Jukema, J Wouter ; Staffler, Guenther ; Princen, Hans M G ; Galabova, Gergana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c392t-4ece367f10f9e0096908e75dcd9e646af19ed900f2bfe689952b1c29d47d54ef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Antibodies - metabolism</topic><topic>Aortic Diseases - prevention & control</topic><topic>Apolipoprotein E3 - deficiency</topic><topic>Atherosclerosis - prevention & control</topic><topic>Basic Science</topic><topic>Biomarkers - metabolism</topic><topic>Cholesterol, HDL - metabolism</topic><topic>Coronary Disease - prevention & control</topic><topic>Disease Models, Animal</topic><topic>Editor's Choice</topic><topic>Female</topic><topic>Hypercholesterolemia - immunology</topic><topic>Hypercholesterolemia - prevention & control</topic><topic>Intercellular Adhesion Molecule-1 - metabolism</topic><topic>Mice, Transgenic</topic><topic>NLR Family, Pyrin Domain-Containing 3 Protein - immunology</topic><topic>NLR Family, Pyrin Domain-Containing 3 Protein - metabolism</topic><topic>PCSK9 Inhibitors</topic><topic>Plaque, Atherosclerotic - prevention & control</topic><topic>Proprotein Convertase 9 - immunology</topic><topic>Vaccines, Subunit - administration & dosage</topic><topic>Vaccines, Subunit - immunology</topic><topic>Vasculitis - immunology</topic><topic>Vasculitis - prevention & control</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Landlinger, Christine</creatorcontrib><creatorcontrib>Pouwer, Marianne G</creatorcontrib><creatorcontrib>Juno, Claudia</creatorcontrib><creatorcontrib>van der Hoorn, José W A</creatorcontrib><creatorcontrib>Pieterman, Elsbet J</creatorcontrib><creatorcontrib>Jukema, J Wouter</creatorcontrib><creatorcontrib>Staffler, Guenther</creatorcontrib><creatorcontrib>Princen, Hans M G</creatorcontrib><creatorcontrib>Galabova, Gergana</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>European heart journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Landlinger, Christine</au><au>Pouwer, Marianne G</au><au>Juno, Claudia</au><au>van der Hoorn, José W A</au><au>Pieterman, Elsbet J</au><au>Jukema, J Wouter</au><au>Staffler, Guenther</au><au>Princen, Hans M G</au><au>Galabova, Gergana</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE3Leiden.CETP mice</atitle><jtitle>European heart journal</jtitle><addtitle>Eur Heart J</addtitle><date>2017-08-21</date><risdate>2017</risdate><volume>38</volume><issue>32</issue><spage>2499</spage><epage>2507</epage><pages>2499-2507</pages><issn>0195-668X</issn><eissn>1522-9645</eissn><abstract>Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher risk of atherosclerosis. In this study, the AT04A anti-PCSK9 vaccine was evaluated for its therapeutic potential in ameliorating or even preventing coronary heart disease in the atherogenic APOE*3Leiden.CETP mouse model.
Control and AT04A vaccine-treated mice were fed western-type diet for 18 weeks. Antibody titres, plasma lipids, and inflammatory markers were monitored by ELISA, FPLC, and multiplexed immunoassay, respectively. The progression of atherosclerosis was evaluated by histological analysis of serial cross-sections from the aortic sinus. The AT04A vaccine induced high and persistent antibody levels against PCSK9, causing a significant reduction in plasma total cholesterol (-53%, P < 0.001) and LDLc compared with controls. Plasma inflammatory markers such as serum amyloid A (SAA), macrophage inflammatory protein-1β (MIP-1β/CCL4), macrophage-derived chemokine (MDC/CCL22), cytokine stem cell factor (SCF), and vascular endothelial growth factor A (VEGF-A) were significantly diminished in AT04A-treated mice. As a consequence, treatment with the AT04A vaccine resulted in a decrease in atherosclerotic lesion area (-64%, P = 0.004) and aortic inflammation as well as in more lesion-free aortic segments (+119%, P = 0.026), compared with control.
AT04A vaccine induces an effective immune response against PCSK9 in APOE*3Leiden.CETP mice, leading to a significant reduction of plasma lipids, systemic and vascular inflammation, and atherosclerotic lesions in the aorta.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>28637178</pmid><doi>10.1093/eurheartj/ehx260</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | European heart journal, 2017-08, Vol.38 (32), p.2499-2507 |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Antibodies - metabolism Aortic Diseases - prevention & control Apolipoprotein E3 - deficiency Atherosclerosis - prevention & control Basic Science Biomarkers - metabolism Cholesterol, HDL - metabolism Coronary Disease - prevention & control Disease Models, Animal Editor's Choice Female Hypercholesterolemia - immunology Hypercholesterolemia - prevention & control Intercellular Adhesion Molecule-1 - metabolism Mice, Transgenic NLR Family, Pyrin Domain-Containing 3 Protein - immunology NLR Family, Pyrin Domain-Containing 3 Protein - metabolism PCSK9 Inhibitors Plaque, Atherosclerotic - prevention & control Proprotein Convertase 9 - immunology Vaccines, Subunit - administration & dosage Vaccines, Subunit - immunology Vasculitis - immunology Vasculitis - prevention & control |
| title | The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE3Leiden.CETP mice |
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