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A key role for the novel coronary artery disease gene JCAD in atherosclerosis via shear stress mechanotransduction
Abstract Aims Genome-wide association studies (GWAS) have consistently identified an association between coronary artery disease (CAD) and a locus on chromosome 10 containing a single gene, JCAD (formerly KIAA1462). However, little is known about the mechanism by which JCAD could influence the devel...
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Published in: | Cardiovascular research 2020-09, Vol.116 (11), p.1863-1874 |
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container_title | Cardiovascular research |
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creator | Douglas, Gillian Mehta, Vedanta Al Haj Zen, Ayman Akoumianakis, Ioannis Goel, Anuj Rashbrook, Victoria S Trelfa, Lucy Donovan, Lucy Drydale, Edward Chuaiphichai, Surawee Antoniades, Charalambos Watkins, Hugh Kyriakou, Theodosios Tzima, Ellie Channon, Keith M |
description | Abstract
Aims
Genome-wide association studies (GWAS) have consistently identified an association between coronary artery disease (CAD) and a locus on chromosome 10 containing a single gene, JCAD (formerly KIAA1462). However, little is known about the mechanism by which JCAD could influence the development of atherosclerosis.
Methods and results
Vascular function was quantified in subjects with CAD by flow-mediated dilatation (FMD) and vasorelaxation responses in isolated blood vessel segments. The JCAD risk allele identified by GWAS was associated with reduced FMD and reduced endothelial-dependent relaxations. To study the impact of loss of Jcad on atherosclerosis, Jcad−/− mice were crossed to an ApoE−/− background and fed a high-fat diet from 6 to16 weeks of age. Loss of Jcad did not affect blood pressure or heart rate. However, Jcad−/−ApoE−/− mice developed significantly less atherosclerosis in the aortic root and the inner curvature of the aortic arch. En face analysis revealed a striking reduction in pro-inflammatory adhesion molecules at sites of disturbed flow on the endothelial cell layer of Jcad−/− mice. Loss of Jcad lead to a reduced recovery perfusion in response to hind limb ischaemia, a model of altered in vivo flow. Knock down of JCAD using siRNA in primary human aortic endothelial cells significantly reduced the response to acute onset of flow, as evidenced by reduced phosphorylation of NF-КB, eNOS, and Akt.
Conclusion
The novel CAD gene JCAD promotes atherosclerotic plaque formation via a role in the endothelial cell shear stress mechanotransduction pathway. |
doi_str_mv | 10.1093/cvr/cvz263 |
format | article |
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Aims
Genome-wide association studies (GWAS) have consistently identified an association between coronary artery disease (CAD) and a locus on chromosome 10 containing a single gene, JCAD (formerly KIAA1462). However, little is known about the mechanism by which JCAD could influence the development of atherosclerosis.
Methods and results
Vascular function was quantified in subjects with CAD by flow-mediated dilatation (FMD) and vasorelaxation responses in isolated blood vessel segments. The JCAD risk allele identified by GWAS was associated with reduced FMD and reduced endothelial-dependent relaxations. To study the impact of loss of Jcad on atherosclerosis, Jcad−/− mice were crossed to an ApoE−/− background and fed a high-fat diet from 6 to16 weeks of age. Loss of Jcad did not affect blood pressure or heart rate. However, Jcad−/−ApoE−/− mice developed significantly less atherosclerosis in the aortic root and the inner curvature of the aortic arch. En face analysis revealed a striking reduction in pro-inflammatory adhesion molecules at sites of disturbed flow on the endothelial cell layer of Jcad−/− mice. Loss of Jcad lead to a reduced recovery perfusion in response to hind limb ischaemia, a model of altered in vivo flow. Knock down of JCAD using siRNA in primary human aortic endothelial cells significantly reduced the response to acute onset of flow, as evidenced by reduced phosphorylation of NF-КB, eNOS, and Akt.
Conclusion
The novel CAD gene JCAD promotes atherosclerotic plaque formation via a role in the endothelial cell shear stress mechanotransduction pathway.</description><identifier>ISSN: 0008-6363</identifier><identifier>ISSN: 1755-3245</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvz263</identifier><identifier>PMID: 31584065</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Animals ; Aorta - metabolism ; Aorta - physiopathology ; Aortic Diseases - genetics ; Aortic Diseases - metabolism ; Aortic Diseases - physiopathology ; Aortic Diseases - prevention & control ; Atherosclerosis - genetics ; Atherosclerosis - metabolism ; Atherosclerosis - physiopathology ; Atherosclerosis - prevention & control ; Cell Adhesion Molecules - genetics ; Cell Adhesion Molecules - metabolism ; Cells, Cultured ; Coronary Artery Disease - genetics ; Coronary Artery Disease - metabolism ; Coronary Artery Disease - physiopathology ; Coronary Circulation ; Coronary Vessels - metabolism ; Coronary Vessels - physiopathology ; Disease Models, Animal ; Endothelium, Vascular - metabolism ; Endothelium, Vascular - physiopathology ; Genome-Wide Association Study ; Hindlimb - blood supply ; Humans ; Ischemia - genetics ; Ischemia - metabolism ; Ischemia - physiopathology ; Male ; Mechanotransduction, Cellular ; Mice, Inbred C57BL ; Mice, Knockout, ApoE ; NF-kappa B - metabolism ; Nitric Oxide Synthase Type III - metabolism ; Phosphorylation ; Plaque, Atherosclerotic ; Proto-Oncogene Proteins c-akt ; Review Series from the Naples 2019 Joint Meeting of the ESC Working Groups on Myocardial Function and Cellular Biology of the Heart ; Stress, Mechanical</subject><ispartof>Cardiovascular research, 2020-09, Vol.116 (11), p.1863-1874</ispartof><rights>The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology 2019</rights><rights>The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-4b26f83cc6efb3e49dff59fee74b1dc02886307fe208fcee89fc2e5f0c1bb3f93</citedby><cites>FETCH-LOGICAL-c408t-4b26f83cc6efb3e49dff59fee74b1dc02886307fe208fcee89fc2e5f0c1bb3f93</cites><orcidid>0000-0002-5287-9016 ; 0000-0002-8667-3032 ; 0000-0003-2307-4021 ; 0000-0002-4674-0210 ; 0000-0003-4357-2546 ; 0000-0002-9090-5326 ; 0000-0002-6983-5423 ; 0000-0002-2145-2925 ; 0000-0002-1043-4342</orcidid></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/31584065$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Douglas, Gillian</creatorcontrib><creatorcontrib>Mehta, Vedanta</creatorcontrib><creatorcontrib>Al Haj Zen, Ayman</creatorcontrib><creatorcontrib>Akoumianakis, Ioannis</creatorcontrib><creatorcontrib>Goel, Anuj</creatorcontrib><creatorcontrib>Rashbrook, Victoria S</creatorcontrib><creatorcontrib>Trelfa, Lucy</creatorcontrib><creatorcontrib>Donovan, Lucy</creatorcontrib><creatorcontrib>Drydale, Edward</creatorcontrib><creatorcontrib>Chuaiphichai, Surawee</creatorcontrib><creatorcontrib>Antoniades, Charalambos</creatorcontrib><creatorcontrib>Watkins, Hugh</creatorcontrib><creatorcontrib>Kyriakou, Theodosios</creatorcontrib><creatorcontrib>Tzima, Ellie</creatorcontrib><creatorcontrib>Channon, Keith M</creatorcontrib><title>A key role for the novel coronary artery disease gene JCAD in atherosclerosis via shear stress mechanotransduction</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>Abstract
Aims
Genome-wide association studies (GWAS) have consistently identified an association between coronary artery disease (CAD) and a locus on chromosome 10 containing a single gene, JCAD (formerly KIAA1462). However, little is known about the mechanism by which JCAD could influence the development of atherosclerosis.
Methods and results
Vascular function was quantified in subjects with CAD by flow-mediated dilatation (FMD) and vasorelaxation responses in isolated blood vessel segments. The JCAD risk allele identified by GWAS was associated with reduced FMD and reduced endothelial-dependent relaxations. To study the impact of loss of Jcad on atherosclerosis, Jcad−/− mice were crossed to an ApoE−/− background and fed a high-fat diet from 6 to16 weeks of age. Loss of Jcad did not affect blood pressure or heart rate. However, Jcad−/−ApoE−/− mice developed significantly less atherosclerosis in the aortic root and the inner curvature of the aortic arch. En face analysis revealed a striking reduction in pro-inflammatory adhesion molecules at sites of disturbed flow on the endothelial cell layer of Jcad−/− mice. Loss of Jcad lead to a reduced recovery perfusion in response to hind limb ischaemia, a model of altered in vivo flow. Knock down of JCAD using siRNA in primary human aortic endothelial cells significantly reduced the response to acute onset of flow, as evidenced by reduced phosphorylation of NF-КB, eNOS, and Akt.
Conclusion
The novel CAD gene JCAD promotes atherosclerotic plaque formation via a role in the endothelial cell shear stress mechanotransduction pathway.</description><subject>Animals</subject><subject>Aorta - metabolism</subject><subject>Aorta - physiopathology</subject><subject>Aortic Diseases - genetics</subject><subject>Aortic Diseases - metabolism</subject><subject>Aortic Diseases - physiopathology</subject><subject>Aortic Diseases - prevention & control</subject><subject>Atherosclerosis - genetics</subject><subject>Atherosclerosis - metabolism</subject><subject>Atherosclerosis - physiopathology</subject><subject>Atherosclerosis - prevention & control</subject><subject>Cell Adhesion Molecules - genetics</subject><subject>Cell Adhesion Molecules - metabolism</subject><subject>Cells, Cultured</subject><subject>Coronary Artery Disease - genetics</subject><subject>Coronary Artery Disease - metabolism</subject><subject>Coronary Artery Disease - physiopathology</subject><subject>Coronary Circulation</subject><subject>Coronary Vessels - metabolism</subject><subject>Coronary Vessels - physiopathology</subject><subject>Disease Models, Animal</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Endothelium, Vascular - physiopathology</subject><subject>Genome-Wide Association Study</subject><subject>Hindlimb - blood supply</subject><subject>Humans</subject><subject>Ischemia - genetics</subject><subject>Ischemia - metabolism</subject><subject>Ischemia - physiopathology</subject><subject>Male</subject><subject>Mechanotransduction, Cellular</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout, ApoE</subject><subject>NF-kappa B - metabolism</subject><subject>Nitric Oxide Synthase Type III - metabolism</subject><subject>Phosphorylation</subject><subject>Plaque, Atherosclerotic</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Review Series from the Naples 2019 Joint Meeting of the ESC Working Groups on Myocardial Function and Cellular Biology of the Heart</subject><subject>Stress, Mechanical</subject><issn>0008-6363</issn><issn>1755-3245</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><recordid>eNp9kUtLAzEUhYMotlY3_gDJRhBhNDNJ5rERSn0juNF1yGRubHSa1GRmoP56U6qiGxfJJdyPc0_uQegwJWcpqei5Gnw8H1lOt9A4LThPaMb4NhoTQsokpzkdob0QXuOT84LtohFNeclIzsfIT_EbrLB3LWDtPO7mgK0boMXKeWelX2HpO4ilMQFkAPwCFvD9bHqJjcUy8t4F1a5vE_BgJA5zkB6HzkMIeAFqLq3rvLSh6VVnnN1HO1q2AQ6-6gQ9X189zW6Th8ebu9n0IVGMlF3C6izXJVUqB11TYFWjNa80QMHqtFEkK8uckkJDRkqtAMpKqwy4Jiqta6orOkEXG91lXy-gUWCji1YsvVnEbwknjfjbsWYuXtwgCsYqnpMocPIl4N17D6ETCxMUtK204PogMkpStraxnnW6QVXcQ_Cgf8akRKxDEjEksQkpwke_jf2g36lE4HgDuH75n9AnKb-ffQ</recordid><startdate>20200901</startdate><enddate>20200901</enddate><creator>Douglas, Gillian</creator><creator>Mehta, Vedanta</creator><creator>Al Haj Zen, Ayman</creator><creator>Akoumianakis, Ioannis</creator><creator>Goel, Anuj</creator><creator>Rashbrook, Victoria S</creator><creator>Trelfa, Lucy</creator><creator>Donovan, Lucy</creator><creator>Drydale, Edward</creator><creator>Chuaiphichai, Surawee</creator><creator>Antoniades, Charalambos</creator><creator>Watkins, Hugh</creator><creator>Kyriakou, Theodosios</creator><creator>Tzima, Ellie</creator><creator>Channon, Keith M</creator><general>Oxford University Press</general><scope>TOX</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5287-9016</orcidid><orcidid>https://orcid.org/0000-0002-8667-3032</orcidid><orcidid>https://orcid.org/0000-0003-2307-4021</orcidid><orcidid>https://orcid.org/0000-0002-4674-0210</orcidid><orcidid>https://orcid.org/0000-0003-4357-2546</orcidid><orcidid>https://orcid.org/0000-0002-9090-5326</orcidid><orcidid>https://orcid.org/0000-0002-6983-5423</orcidid><orcidid>https://orcid.org/0000-0002-2145-2925</orcidid><orcidid>https://orcid.org/0000-0002-1043-4342</orcidid></search><sort><creationdate>20200901</creationdate><title>A key role for the novel coronary artery disease gene JCAD in atherosclerosis via shear stress mechanotransduction</title><author>Douglas, Gillian ; Mehta, Vedanta ; Al Haj Zen, Ayman ; Akoumianakis, Ioannis ; Goel, Anuj ; Rashbrook, Victoria S ; Trelfa, Lucy ; Donovan, Lucy ; Drydale, Edward ; Chuaiphichai, Surawee ; Antoniades, Charalambos ; Watkins, Hugh ; Kyriakou, Theodosios ; Tzima, Ellie ; Channon, Keith M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-4b26f83cc6efb3e49dff59fee74b1dc02886307fe208fcee89fc2e5f0c1bb3f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Aorta - metabolism</topic><topic>Aorta - physiopathology</topic><topic>Aortic Diseases - genetics</topic><topic>Aortic Diseases - metabolism</topic><topic>Aortic Diseases - physiopathology</topic><topic>Aortic Diseases - prevention & control</topic><topic>Atherosclerosis - genetics</topic><topic>Atherosclerosis - metabolism</topic><topic>Atherosclerosis - physiopathology</topic><topic>Atherosclerosis - prevention & control</topic><topic>Cell Adhesion Molecules - genetics</topic><topic>Cell Adhesion Molecules - metabolism</topic><topic>Cells, Cultured</topic><topic>Coronary Artery Disease - genetics</topic><topic>Coronary Artery Disease - metabolism</topic><topic>Coronary Artery Disease - physiopathology</topic><topic>Coronary Circulation</topic><topic>Coronary Vessels - metabolism</topic><topic>Coronary Vessels - physiopathology</topic><topic>Disease Models, Animal</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Endothelium, Vascular - physiopathology</topic><topic>Genome-Wide Association Study</topic><topic>Hindlimb - blood supply</topic><topic>Humans</topic><topic>Ischemia - genetics</topic><topic>Ischemia - metabolism</topic><topic>Ischemia - physiopathology</topic><topic>Male</topic><topic>Mechanotransduction, Cellular</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout, ApoE</topic><topic>NF-kappa B - metabolism</topic><topic>Nitric Oxide Synthase Type III - metabolism</topic><topic>Phosphorylation</topic><topic>Plaque, Atherosclerotic</topic><topic>Proto-Oncogene Proteins c-akt</topic><topic>Review Series from the Naples 2019 Joint Meeting of the ESC Working Groups on Myocardial Function and Cellular Biology of the Heart</topic><topic>Stress, Mechanical</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Douglas, Gillian</creatorcontrib><creatorcontrib>Mehta, Vedanta</creatorcontrib><creatorcontrib>Al Haj Zen, Ayman</creatorcontrib><creatorcontrib>Akoumianakis, Ioannis</creatorcontrib><creatorcontrib>Goel, Anuj</creatorcontrib><creatorcontrib>Rashbrook, Victoria S</creatorcontrib><creatorcontrib>Trelfa, Lucy</creatorcontrib><creatorcontrib>Donovan, Lucy</creatorcontrib><creatorcontrib>Drydale, Edward</creatorcontrib><creatorcontrib>Chuaiphichai, Surawee</creatorcontrib><creatorcontrib>Antoniades, Charalambos</creatorcontrib><creatorcontrib>Watkins, Hugh</creatorcontrib><creatorcontrib>Kyriakou, Theodosios</creatorcontrib><creatorcontrib>Tzima, Ellie</creatorcontrib><creatorcontrib>Channon, Keith M</creatorcontrib><collection>Oxford Academic Journals (Open Access)</collection><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>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Douglas, Gillian</au><au>Mehta, Vedanta</au><au>Al Haj Zen, Ayman</au><au>Akoumianakis, Ioannis</au><au>Goel, Anuj</au><au>Rashbrook, Victoria S</au><au>Trelfa, Lucy</au><au>Donovan, Lucy</au><au>Drydale, Edward</au><au>Chuaiphichai, Surawee</au><au>Antoniades, Charalambos</au><au>Watkins, Hugh</au><au>Kyriakou, Theodosios</au><au>Tzima, Ellie</au><au>Channon, Keith M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A key role for the novel coronary artery disease gene JCAD in atherosclerosis via shear stress mechanotransduction</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2020-09-01</date><risdate>2020</risdate><volume>116</volume><issue>11</issue><spage>1863</spage><epage>1874</epage><pages>1863-1874</pages><issn>0008-6363</issn><issn>1755-3245</issn><eissn>1755-3245</eissn><abstract>Abstract
Aims
Genome-wide association studies (GWAS) have consistently identified an association between coronary artery disease (CAD) and a locus on chromosome 10 containing a single gene, JCAD (formerly KIAA1462). However, little is known about the mechanism by which JCAD could influence the development of atherosclerosis.
Methods and results
Vascular function was quantified in subjects with CAD by flow-mediated dilatation (FMD) and vasorelaxation responses in isolated blood vessel segments. The JCAD risk allele identified by GWAS was associated with reduced FMD and reduced endothelial-dependent relaxations. To study the impact of loss of Jcad on atherosclerosis, Jcad−/− mice were crossed to an ApoE−/− background and fed a high-fat diet from 6 to16 weeks of age. Loss of Jcad did not affect blood pressure or heart rate. However, Jcad−/−ApoE−/− mice developed significantly less atherosclerosis in the aortic root and the inner curvature of the aortic arch. En face analysis revealed a striking reduction in pro-inflammatory adhesion molecules at sites of disturbed flow on the endothelial cell layer of Jcad−/− mice. Loss of Jcad lead to a reduced recovery perfusion in response to hind limb ischaemia, a model of altered in vivo flow. Knock down of JCAD using siRNA in primary human aortic endothelial cells significantly reduced the response to acute onset of flow, as evidenced by reduced phosphorylation of NF-КB, eNOS, and Akt.
Conclusion
The novel CAD gene JCAD promotes atherosclerotic plaque formation via a role in the endothelial cell shear stress mechanotransduction pathway.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>31584065</pmid><doi>10.1093/cvr/cvz263</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-5287-9016</orcidid><orcidid>https://orcid.org/0000-0002-8667-3032</orcidid><orcidid>https://orcid.org/0000-0003-2307-4021</orcidid><orcidid>https://orcid.org/0000-0002-4674-0210</orcidid><orcidid>https://orcid.org/0000-0003-4357-2546</orcidid><orcidid>https://orcid.org/0000-0002-9090-5326</orcidid><orcidid>https://orcid.org/0000-0002-6983-5423</orcidid><orcidid>https://orcid.org/0000-0002-2145-2925</orcidid><orcidid>https://orcid.org/0000-0002-1043-4342</orcidid><oa>free_for_read</oa></addata></record> |
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source | Oxford Journals Online |
subjects | Animals Aorta - metabolism Aorta - physiopathology Aortic Diseases - genetics Aortic Diseases - metabolism Aortic Diseases - physiopathology Aortic Diseases - prevention & control Atherosclerosis - genetics Atherosclerosis - metabolism Atherosclerosis - physiopathology Atherosclerosis - prevention & control Cell Adhesion Molecules - genetics Cell Adhesion Molecules - metabolism Cells, Cultured Coronary Artery Disease - genetics Coronary Artery Disease - metabolism Coronary Artery Disease - physiopathology Coronary Circulation Coronary Vessels - metabolism Coronary Vessels - physiopathology Disease Models, Animal Endothelium, Vascular - metabolism Endothelium, Vascular - physiopathology Genome-Wide Association Study Hindlimb - blood supply Humans Ischemia - genetics Ischemia - metabolism Ischemia - physiopathology Male Mechanotransduction, Cellular Mice, Inbred C57BL Mice, Knockout, ApoE NF-kappa B - metabolism Nitric Oxide Synthase Type III - metabolism Phosphorylation Plaque, Atherosclerotic Proto-Oncogene Proteins c-akt Review Series from the Naples 2019 Joint Meeting of the ESC Working Groups on Myocardial Function and Cellular Biology of the Heart Stress, Mechanical |
title | A key role for the novel coronary artery disease gene JCAD in atherosclerosis via shear stress mechanotransduction |
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