Recombinant Decorin Fusion Protein Attenuates Murine Abdominal Aortic Aneurysm Formation and Rupture
Decorin (DCN) is a small-leucine rich proteoglycan that mediates collagen fibrillogenesis, organization, and tensile strength. Adventitial DCN is reduced in abdominal aortic aneurysm (AAA) resulting in vessel wall instability thereby predisposing the vessel to rupture. Recombinant DCN fusion protein...
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| creator | Shen, Yue Russo, Valerio Zeglinski, Matthew R. Sellers, Stephanie L. Wu, Zhengguo Oram, Cameron Santacruz, Stephanie Merkulova, Yulia Turner, Christopher Tauh, Keerit Zhao, Hongyan Bozin, Tatjana Bohunek, Lubos Zeng, Haishan Seidman, Michael A. Bleackley, R. Chris McManus, Bruce M. Ruoslahti, Erkki Järvinen, Tero A. H. Granville, David J. |
| description | Decorin (DCN) is a small-leucine rich proteoglycan that mediates collagen fibrillogenesis, organization, and tensile strength. Adventitial DCN is reduced in abdominal aortic aneurysm (AAA) resulting in vessel wall instability thereby predisposing the vessel to rupture. Recombinant DCN fusion protein CAR-DCN was engineered with an extended C-terminus comprised of CAR homing peptide that recognizes inflamed blood vessels and penetrates deep into the vessel wall. In the present study, the role of systemically-administered CAR-DCN in AAA progression and rupture was assessed in a murine model. Apolipoprotein E knockout (ApoE-KO) mice were infused with angiotensin II (AngII) for 28 days to induce AAA formation. CAR-DCN or vehicle was administrated systemically until day 15. Mortality due to AAA rupture was significantly reduced in CAR-DCN-treated mice compared to controls. Although the prevalence of AAA was similar between vehicle and CAR-DCN groups, the severity of AAA in the CAR-DCN group was significantly reduced. Histological analysis revealed that CAR-DCN treatment significantly increased DCN and collagen levels within the aortic wall as compared to vehicle controls. Taken together, these results suggest that CAR-DCN treatment attenuates the formation and rupture of Ang II-induced AAA in mice by reinforcing the aortic wall. |
| doi_str_mv | 10.1038/s41598-017-16194-8 |
| format | Article |
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Chris ; McManus, Bruce M. ; Ruoslahti, Erkki ; Järvinen, Tero A. H. ; Granville, David J.</creator><creatorcontrib>Shen, Yue ; Russo, Valerio ; Zeglinski, Matthew R. ; Sellers, Stephanie L. ; Wu, Zhengguo ; Oram, Cameron ; Santacruz, Stephanie ; Merkulova, Yulia ; Turner, Christopher ; Tauh, Keerit ; Zhao, Hongyan ; Bozin, Tatjana ; Bohunek, Lubos ; Zeng, Haishan ; Seidman, Michael A. ; Bleackley, R. Chris ; McManus, Bruce M. ; Ruoslahti, Erkki ; Järvinen, Tero A. H. ; Granville, David J.</creatorcontrib><description>Decorin (DCN) is a small-leucine rich proteoglycan that mediates collagen fibrillogenesis, organization, and tensile strength. Adventitial DCN is reduced in abdominal aortic aneurysm (AAA) resulting in vessel wall instability thereby predisposing the vessel to rupture. Recombinant DCN fusion protein CAR-DCN was engineered with an extended C-terminus comprised of CAR homing peptide that recognizes inflamed blood vessels and penetrates deep into the vessel wall. In the present study, the role of systemically-administered CAR-DCN in AAA progression and rupture was assessed in a murine model. Apolipoprotein E knockout (ApoE-KO) mice were infused with angiotensin II (AngII) for 28 days to induce AAA formation. CAR-DCN or vehicle was administrated systemically until day 15. Mortality due to AAA rupture was significantly reduced in CAR-DCN-treated mice compared to controls. Although the prevalence of AAA was similar between vehicle and CAR-DCN groups, the severity of AAA in the CAR-DCN group was significantly reduced. Histological analysis revealed that CAR-DCN treatment significantly increased DCN and collagen levels within the aortic wall as compared to vehicle controls. Taken together, these results suggest that CAR-DCN treatment attenuates the formation and rupture of Ang II-induced AAA in mice by reinforcing the aortic wall.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-017-16194-8</identifier><identifier>PMID: 29158532</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/51 ; 631/154 ; 64/60 ; 692/4019/592/75/593/1287 ; Aneurysms ; Angiotensin ; Angiotensin II ; Angiotensin II - genetics ; Animal models ; Animals ; Aortic Aneurysm, Abdominal - chemically induced ; Aortic Aneurysm, Abdominal - genetics ; Aortic Aneurysm, Abdominal - physiopathology ; Aortic aneurysms ; Apolipoprotein E ; Apolipoproteins E - genetics ; Blood vessels ; C-Terminus ; Collagen ; Decorin ; Decorin - genetics ; Disease Models, Animal ; Fibrillogenesis ; Fusion protein ; Humanities and Social Sciences ; Humans ; Inflammation ; Leucine ; Mice ; Mice, Knockout ; multidisciplinary ; Recombinant Proteins - administration & dosage ; Recombinant Proteins - genetics ; Rodents ; Rupture ; Science ; Science (multidisciplinary)</subject><ispartof>Scientific reports, 2017-11, Vol.7 (1), p.15857-9, Article 15857</ispartof><rights>The Author(s) 2017</rights><rights>2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-358e3401b7d83160c22a72c0f562881af144d38c3516d5d06e5272165bb85843</citedby><cites>FETCH-LOGICAL-c474t-358e3401b7d83160c22a72c0f562881af144d38c3516d5d06e5272165bb85843</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696466/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696466/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29158532$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shen, Yue</creatorcontrib><creatorcontrib>Russo, Valerio</creatorcontrib><creatorcontrib>Zeglinski, Matthew R.</creatorcontrib><creatorcontrib>Sellers, Stephanie L.</creatorcontrib><creatorcontrib>Wu, Zhengguo</creatorcontrib><creatorcontrib>Oram, Cameron</creatorcontrib><creatorcontrib>Santacruz, Stephanie</creatorcontrib><creatorcontrib>Merkulova, Yulia</creatorcontrib><creatorcontrib>Turner, Christopher</creatorcontrib><creatorcontrib>Tauh, Keerit</creatorcontrib><creatorcontrib>Zhao, Hongyan</creatorcontrib><creatorcontrib>Bozin, Tatjana</creatorcontrib><creatorcontrib>Bohunek, Lubos</creatorcontrib><creatorcontrib>Zeng, Haishan</creatorcontrib><creatorcontrib>Seidman, Michael A.</creatorcontrib><creatorcontrib>Bleackley, R. Chris</creatorcontrib><creatorcontrib>McManus, Bruce M.</creatorcontrib><creatorcontrib>Ruoslahti, Erkki</creatorcontrib><creatorcontrib>Järvinen, Tero A. H.</creatorcontrib><creatorcontrib>Granville, David J.</creatorcontrib><title>Recombinant Decorin Fusion Protein Attenuates Murine Abdominal Aortic Aneurysm Formation and Rupture</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Decorin (DCN) is a small-leucine rich proteoglycan that mediates collagen fibrillogenesis, organization, and tensile strength. Adventitial DCN is reduced in abdominal aortic aneurysm (AAA) resulting in vessel wall instability thereby predisposing the vessel to rupture. Recombinant DCN fusion protein CAR-DCN was engineered with an extended C-terminus comprised of CAR homing peptide that recognizes inflamed blood vessels and penetrates deep into the vessel wall. In the present study, the role of systemically-administered CAR-DCN in AAA progression and rupture was assessed in a murine model. Apolipoprotein E knockout (ApoE-KO) mice were infused with angiotensin II (AngII) for 28 days to induce AAA formation. CAR-DCN or vehicle was administrated systemically until day 15. Mortality due to AAA rupture was significantly reduced in CAR-DCN-treated mice compared to controls. Although the prevalence of AAA was similar between vehicle and CAR-DCN groups, the severity of AAA in the CAR-DCN group was significantly reduced. Histological analysis revealed that CAR-DCN treatment significantly increased DCN and collagen levels within the aortic wall as compared to vehicle controls. Taken together, these results suggest that CAR-DCN treatment attenuates the formation and rupture of Ang II-induced AAA in mice by reinforcing the aortic wall.</description><subject>13/51</subject><subject>631/154</subject><subject>64/60</subject><subject>692/4019/592/75/593/1287</subject><subject>Aneurysms</subject><subject>Angiotensin</subject><subject>Angiotensin II</subject><subject>Angiotensin II - genetics</subject><subject>Animal models</subject><subject>Animals</subject><subject>Aortic Aneurysm, Abdominal - chemically induced</subject><subject>Aortic Aneurysm, Abdominal - genetics</subject><subject>Aortic Aneurysm, Abdominal - physiopathology</subject><subject>Aortic aneurysms</subject><subject>Apolipoprotein E</subject><subject>Apolipoproteins E - genetics</subject><subject>Blood vessels</subject><subject>C-Terminus</subject><subject>Collagen</subject><subject>Decorin</subject><subject>Decorin - genetics</subject><subject>Disease Models, Animal</subject><subject>Fibrillogenesis</subject><subject>Fusion protein</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Leucine</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>multidisciplinary</subject><subject>Recombinant Proteins - administration & dosage</subject><subject>Recombinant Proteins - genetics</subject><subject>Rodents</subject><subject>Rupture</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1UUtrGzEQFiWlMWn-QA9FkPM2Gr1WewksTt0EUlpM7kK7K7sbvJKjR8D_vnLtBucQXTTD95gZPoS-APkGhKnryEE0qiJQVyCh4ZX6gGaUcFFRRunZSX2OLmN8IuUJ2nBoPqFz2oBQgtEZGpa291M3OuMSvi11GB1e5Dh6h38Hn2xp25SsyybZiH_mglvcdoOfimaDWx_S2OPW2Rx2ccILHyaT9mrjBrzM25SD_Yw-rswm2svjf4EeF98f53fVw68f9_P2oep5zVPFhLKME-jqQTGQpKfU1LQnKyGpUmBWwPnAVM8EyEEMRFpBawpSdJ0SirMLdHOw3eZuskNvXQpmo7dhnEzYaW9G_RZx4x-99i9ayEZyKYvB1dEg-OdsY9JPPodyZtTQSMlJA7QuLHpg9cHHGOzqdQIQvc9GH7LRJRv9Lxutiujr6W6vkv9JFAI7EGKB3NqGk9nv2_4F9lmahQ</recordid><startdate>20171120</startdate><enddate>20171120</enddate><creator>Shen, Yue</creator><creator>Russo, Valerio</creator><creator>Zeglinski, Matthew R.</creator><creator>Sellers, Stephanie L.</creator><creator>Wu, Zhengguo</creator><creator>Oram, Cameron</creator><creator>Santacruz, Stephanie</creator><creator>Merkulova, Yulia</creator><creator>Turner, Christopher</creator><creator>Tauh, Keerit</creator><creator>Zhao, Hongyan</creator><creator>Bozin, Tatjana</creator><creator>Bohunek, Lubos</creator><creator>Zeng, Haishan</creator><creator>Seidman, Michael A.</creator><creator>Bleackley, R. 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Chris</au><au>McManus, Bruce M.</au><au>Ruoslahti, Erkki</au><au>Järvinen, Tero A. H.</au><au>Granville, David J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Recombinant Decorin Fusion Protein Attenuates Murine Abdominal Aortic Aneurysm Formation and Rupture</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2017-11-20</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>15857</spage><epage>9</epage><pages>15857-9</pages><artnum>15857</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Decorin (DCN) is a small-leucine rich proteoglycan that mediates collagen fibrillogenesis, organization, and tensile strength. Adventitial DCN is reduced in abdominal aortic aneurysm (AAA) resulting in vessel wall instability thereby predisposing the vessel to rupture. Recombinant DCN fusion protein CAR-DCN was engineered with an extended C-terminus comprised of CAR homing peptide that recognizes inflamed blood vessels and penetrates deep into the vessel wall. In the present study, the role of systemically-administered CAR-DCN in AAA progression and rupture was assessed in a murine model. Apolipoprotein E knockout (ApoE-KO) mice were infused with angiotensin II (AngII) for 28 days to induce AAA formation. CAR-DCN or vehicle was administrated systemically until day 15. Mortality due to AAA rupture was significantly reduced in CAR-DCN-treated mice compared to controls. Although the prevalence of AAA was similar between vehicle and CAR-DCN groups, the severity of AAA in the CAR-DCN group was significantly reduced. Histological analysis revealed that CAR-DCN treatment significantly increased DCN and collagen levels within the aortic wall as compared to vehicle controls. Taken together, these results suggest that CAR-DCN treatment attenuates the formation and rupture of Ang II-induced AAA in mice by reinforcing the aortic wall.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29158532</pmid><doi>10.1038/s41598-017-16194-8</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13/51 631/154 64/60 692/4019/592/75/593/1287 Aneurysms Angiotensin Angiotensin II Angiotensin II - genetics Animal models Animals Aortic Aneurysm, Abdominal - chemically induced Aortic Aneurysm, Abdominal - genetics Aortic Aneurysm, Abdominal - physiopathology Aortic aneurysms Apolipoprotein E Apolipoproteins E - genetics Blood vessels C-Terminus Collagen Decorin Decorin - genetics Disease Models, Animal Fibrillogenesis Fusion protein Humanities and Social Sciences Humans Inflammation Leucine Mice Mice, Knockout multidisciplinary Recombinant Proteins - administration & dosage Recombinant Proteins - genetics Rodents Rupture Science Science (multidisciplinary) |
| title | Recombinant Decorin Fusion Protein Attenuates Murine Abdominal Aortic Aneurysm Formation and Rupture |
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