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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
Main Authors: 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
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cited_by cdi_FETCH-LOGICAL-c408t-4b26f83cc6efb3e49dff59fee74b1dc02886307fe208fcee89fc2e5f0c1bb3f93
cites cdi_FETCH-LOGICAL-c408t-4b26f83cc6efb3e49dff59fee74b1dc02886307fe208fcee89fc2e5f0c1bb3f93
container_end_page 1874
container_issue 11
container_start_page 1863
container_title Cardiovascular research
container_volume 116
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
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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 &amp; control ; Atherosclerosis - genetics ; Atherosclerosis - metabolism ; Atherosclerosis - physiopathology ; Atherosclerosis - prevention &amp; 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 &amp; control</subject><subject>Atherosclerosis - genetics</subject><subject>Atherosclerosis - metabolism</subject><subject>Atherosclerosis - physiopathology</subject><subject>Atherosclerosis - prevention &amp; 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 &amp; control</topic><topic>Atherosclerosis - genetics</topic><topic>Atherosclerosis - metabolism</topic><topic>Atherosclerosis - physiopathology</topic><topic>Atherosclerosis - prevention &amp; 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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