{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T21:11:58Z","timestamp":1791061918737,"version":"4.1.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2014,5,22]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Although increased amounts of reactive oxygen species in the pathogenesis of abdominal aortic aneurysm (\n              <jats:styled-content style=\"fixed-case\">AAA<\/jats:styled-content>\n              ) are well documented, the precise molecular mechanisms by which reactive oxygen species induce\n              <jats:styled-content style=\"fixed-case\">AAAs<\/jats:styled-content>\n              have not been fully elucidated. This study focused on the role of hydrogen peroxide\u2013inducible clone 5 (Hic\u20105), which is induced by hydrogen peroxide and transforming growth factor\u2010\u03b2, in the cellular signaling of\n              <jats:styled-content style=\"fixed-case\">AAA<\/jats:styled-content>\n              pathogenesis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Using the angiotensin\n              <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\n              \u2013induced\n              <jats:styled-content style=\"fixed-case\">AAA<\/jats:styled-content>\n              model in\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice, we showed that\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              <jats:italic>Hic\u20105<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice were completely protected from\n              <jats:styled-content style=\"fixed-case\">AAA<\/jats:styled-content>\n              formation and aortic rupture, whereas\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice were not. These features were similarly observed in smooth muscle cell\u2013specific Hic\u20105\u2013deficient mice. Furthermore, angiotensin\n              <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\n              treatment induced Hic\u20105 expression in a reactive oxygen species\u2013dependent manner in aortic smooth muscle cells in the early stage of\n              <jats:styled-content style=\"fixed-case\">AAA<\/jats:styled-content>\n              development. Mechanistic studies revealed that Hic\u20105 interacted specifically with c\u2010Jun N\u2010terminal kinase p54 and its upstream regulatory molecule mitogen\u2010activated protein kinase kinase 4 as a novel scaffold protein, resulting in the expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase 2 activation in aortic smooth muscle cells.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Hic\u20105 serves as a novel scaffold protein that specifically activates the mitogen\u2010activated protein kinase kinase 4\/p54 c\u2010Jun N\u2010terminal kinase pathway, thereby leading to the induction and activation of matrix metalloproteinases in smooth muscle cells and subsequent\n              <jats:styled-content style=\"fixed-case\">AAA<\/jats:styled-content>\n              formation. Our study provided a novel therapeutic option aimed at inhibiting the mitogen\u2010activated protein kinase kinase 4\u2013Hic\u20105\u2013p54 c\u2010Jun N\u2010terminal kinase pathway in the vessel wall, particularly through Hic\u20105 inhibition, which may be used to produce more precise and effective therapies.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.113.000747","type":"journal-article","created":{"date-parts":[[2014,5,9]],"date-time":"2014-05-09T09:25:58Z","timestamp":1399627558000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["Identification of Hic\u20135 as a Novel Scaffold for the MKK4\/p54 JNK Pathway in the Development of Abdominal Aortic Aneurysms"],"prefix":"10.1161","volume":"3","author":[{"given":"Xiao\u2010Feng","family":"Lei","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Showa University School of Medicine, Tokyo, 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