{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T01:57:40Z","timestamp":1788919060729,"version":"build-2803163510"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"25","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,6,18]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Atherosclerosis occurs preferentially at the blood vessels encountering blood flow turbulence. The matricellular protein CCN1 is induced in endothelial cells by disturbed flow, and is expressed in advanced atherosclerotic lesions in patients and in the\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mouse model. The role of CCN1 in atherosclerosis remains undefined.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              To assess the function of CCN1 in vivo, knock-in mice carrying the integrin \u03b16\u03b21\u2013binding-defective mutant allele\n              <jats:italic>Ccn1-dm<\/jats:italic>\n              on the\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              background were tested in an atherosclerosis model generated by carotid artery ligation. Additionally, CCN1-regulated functional phenotypes of human umbilical vein endothelial cells, or primary mouse aortic endothelial cells isolated from wild-type and\n              <jats:italic>Ccn1<\/jats:italic>\n              <jats:sup>\n                <jats:italic>dm\/dm<\/jats:italic>\n              <\/jats:sup>\n              mice, were investigated in the in vitro shear stress experiments under unidirectional laminar shear stress (12 dyn\/cm\n              <jats:sup>2<\/jats:sup>\n              ) versus oscillatory shear stress (\u00b15 dyn\/cm\n              <jats:sup>2<\/jats:sup>\n              ) conditions.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We found that\n              <jats:italic>Ccn1<\/jats:italic>\n              expression was upregulated in the arterial endothelium 3 days after ligation before any detectable structural changes, and intensified with the progression of atherosclerotic lesions. Compared with\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              controls,\n              <jats:italic>Ccn1<\/jats:italic>\n              <jats:sup>\n                <jats:italic>dm\/dm<\/jats:italic>\n              <\/jats:sup>\n              \/\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice were remarkably resistant to ligation-induced plaque formation (n=6). These mice exhibited lower oxidative stress, expression of endothelin-1 and monocyte chemoattractant protein-1, and monocyte homing. CCN1\/\u03b16\u03b21 critically mediated flow-induced activation of the pleiotropic transcription factor nuclear factor-\u03baB and therefore the induction of atheroprone gene expression in the mouse arterial endothelium after ligation (n=6), or in cultured human umbilical vein endothelial cells or primary mouse aortic endothelial cells exposed to oscillatory shear stress (n=3 in triplicate). Interestingly, the activation of nuclear factor-\u03baB by CCN1\/\u03b16\u03b21 signaling prompted more production of CCN1 and \u03b16\u03b21. Blocking CCN1-\u03b16\u03b21 binding by the\n              <jats:italic>Ccn1-dm<\/jats:italic>\n              mutation or by T1 peptide (derived from an \u03b16\u03b21-binding sequence of CCN1) disrupted the positive-feedback regulation between CCN1\/\u03b16\u03b21 and nuclear factor-\u03baB, and prevented flow-induced atheroprone phenotypic alterations in endothelial cells or atherosclerosis in mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>These data demonstrate a causative role of CCN1 in atherosclerosis via modulating endothelial phenotypes. CCN1 binds to its receptor integrin \u03b16\u03b21 to activate nuclear factor-\u03baB, thereby instigating a vicious circle to persistently promote atherogenesis. T1, a peptide antagonist selectively targeting CCN1-\u03b16\u03b21, can be further optimized for developing T1-mimetics to treat atherosclerosis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.118.033895","type":"journal-article","created":{"date-parts":[[2019,3,28]],"date-time":"2019-03-28T09:00:37Z","timestamp":1553763637000},"page":"2877-2891","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":75,"title":["Shear-Induced CCN1 Promotes Atheroprone Endothelial Phenotypes and Atherosclerosis"],"prefix":"10.1161","volume":"139","author":[{"given":"Pei-Ling","family":"Hsu","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Anatomy (P.-L.H., J.-S.C., C.-Y.W., F.-E M.), College of Medicine, National Cheng Kung University, Tainan, Taiwan."},{"name":"Institute of Basic Medical Sciences (P.-L.H., H.-L.W., F.-E M.), College of Medicine, National Cheng Kung University, Tainan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jheng-Sin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy (P.-L.H., J.-S.C., C.-Y.W., F.-E M.), College of Medicine, National Cheng Kung University, Tainan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Yung","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy (P.-L.H., J.-S.C., C.-Y.W., F.-E M.), College of Medicine, National Cheng Kung University, Tainan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua-Lin","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences (P.-L.H., H.-L.W., F.-E M.), College of Medicine, National Cheng Kung University, Tainan, Taiwan."},{"name":"Department of Biochemistry and Molecular Biology (H.-L.W.), College of Medicine, National Cheng Kung University, Tainan, 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