{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T06:15:07Z","timestamp":1784614507964,"version":"3.55.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2018,12,7]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>AngII (angiotensin II)-mediated vascular smooth muscle cell (VSMC) dysfunction plays a major role in hypertension. Long noncoding RNAs have elicited much interest, but their molecular roles in AngII actions and hypertension are unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              To investigate the regulation and functions of a novel long noncoding RNA growth factor\u2013 and proinflammatory cytokine\u2013induced vascular cell-expressed RNA (\n              <jats:italic>Giver<\/jats:italic>\n              ), in AngII-mediated VSMC dysfunction.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              RNA-sequencing and real-time quantitative polymerase chain reactions revealed that treatment of rat VSMC with AngII increased the expression of\n              <jats:italic>Giver<\/jats:italic>\n              and\n              <jats:italic>Nr4a3<\/jats:italic>\n              , an adjacent gene encoding a nuclear receptor. Similar changes were observed in rat and mouse aortas treated ex vivo with AngII. RNA-FISH (fluorescence in situ hybridization) and subcellular fractionation showed predominantly nuclear localization of\n              <jats:italic>Giver<\/jats:italic>\n              . AngII increased\n              <jats:italic>Giver<\/jats:italic>\n              expression via recruitment of Nr4a3 to\n              <jats:italic>Giver<\/jats:italic>\n              promoter. Microarray profiling and real-time quantitative polymerase chain reaction validation in VSMC showed that\n              <jats:italic>Giver<\/jats:italic>\n              knockdown attenuated the expression of genes involved in oxidative stress (\n              <jats:italic>Nox1<\/jats:italic>\n              ) and inflammation (\n              <jats:italic>Il6<\/jats:italic>\n              ,\n              <jats:italic>Ccl2<\/jats:italic>\n              ,\n              <jats:italic>Tnf<\/jats:italic>\n              ) but increased\n              <jats:italic>Nr4a3<\/jats:italic>\n              . Conversely, endogenous\n              <jats:italic>Giver<\/jats:italic>\n              overexpression showed opposite effects supporting its role in oxidative stress and inflammation. Chromatin immunoprecipitation assays showed\n              <jats:italic>Giver<\/jats:italic>\n              overexpression also increased Pol II (RNA polymerase II) enrichment and decreased repressive histone modification histone H3 trimethylation on lysine 27 at\n              <jats:italic>Nox1<\/jats:italic>\n              and inflammatory gene promoters. Accordingly,\n              <jats:italic>Giver<\/jats:italic>\n              knockdown inhibited AngII-induced oxidative stress and proliferation in rat VSMC. RNA-pulldown combined with mass spectrometry showed\n              <jats:italic>Giver<\/jats:italic>\n              interacts with nuclear and chromatin remodeling proteins and corepressors, including NONO (non-pou domain-containing octamer-binding protein). Moreover, NONO knockdown elicited similar effects as\n              <jats:italic>Giver<\/jats:italic>\n              knockdown on the expression of key\n              <jats:italic>Giver<\/jats:italic>\n              -regulated genes. Notably,\n              <jats:italic>GIVER<\/jats:italic>\n              and\n              <jats:italic>NR4A3<\/jats:italic>\n              were increased in AngII-treated human VSMC and in arteries from hypertensive patients but attenuated in hypertensive patients treated with ACE (angiotensin-converting enzyme) inhibitors or angiotensin receptor blockers. Furthermore, human\n              <jats:italic>GIVER<\/jats:italic>\n              also exhibits partial functional conservation with rat\n              <jats:italic>Giver<\/jats:italic>\n              .\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              <jats:italic>Giver<\/jats:italic>\n              and its regulator\n              <jats:italic>Nr4a3<\/jats:italic>\n              are important players in AngII-mediated VSMC dysfunction and could be novel targets for antihypertensive therapy.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.118.313207","type":"journal-article","created":{"date-parts":[[2018,12,6]],"date-time":"2018-12-06T19:01:02Z","timestamp":1544122862000},"page":"1298-1312","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":125,"title":["A Novel Angiotensin II\u2013Induced Long Noncoding RNA\n            <i>Giver<\/i>\n            Regulates Oxidative Stress, Inflammation, and Proliferation in Vascular Smooth Muscle Cells"],"prefix":"10.1161","volume":"123","author":[{"given":"Sadhan","family":"Das","sequence":"first","affiliation":[{"name":"From the Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute (S.D., E.Z., P.S., V.A., M.A.R., K.S., A.L., L.L., M.W., Z.C., M.K., H.J.O., R.N.), Beckman Research Institute of City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erli","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute (S.D., E.Z., P.S., V.A., M.A.R., K.S., A.L., L.L., M.W., Z.C., M.K., H.J.O., R.N.), Beckman Research Institute of City of Hope, Duarte, CA"},{"name":"Department of Cardiology (E.Z., Q.G., X.Z., B.Z., H.Z., Q.Z., Y.W.), State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China."},{"name":"Center for Structural Heart Diseases (E.Z., W.W., Y.W.), State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parijat","family":"Senapati","sequence":"additional","affiliation":[{"name":"From the Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute (S.D., E.Z., P.S., V.A., M.A.R., K.S., A.L., L.L., M.W., Z.C., M.K., H.J.O., R.N.), Beckman Research Institute of City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishnu","family":"Amaram","sequence":"additional","affiliation":[{"name":"From the Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute (S.D., E.Z., P.S., V.A., M.A.R., K.S., A.L., L.L., M.W., Z.C., M.K., H.J.O., R.N.), Beckman Research Institute of City of Hope, Duarte, CA"},{"name":"Irell and Manella Graduate School of Biological Sciences (V.A., K.S., R.N.), Beckman Research Institute of City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marpadga A.","family":"Reddy","sequence":"additional","affiliation":[{"name":"From the Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute (S.D., E.Z., P.S., V.A., M.A.R., K.S., A.L., L.L., M.W., Z.C., M.K., H.J.O., R.N.), Beckman Research Institute of City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Stapleton","sequence":"additional","affiliation":[{"name":"From the Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute (S.D., E.Z., P.S., V.A., M.A.R., K.S., A.L., L.L., M.W., Z.C., M.K., H.J.O., R.N.), Beckman Research Institute of City of Hope, Duarte, CA"},{"name":"Irell and Manella Graduate School of Biological Sciences (V.A., K.S., R.N.), Beckman Research Institute of City of Hope, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Leung","sequence":"additional","affiliation":[{"name":"From the Department of 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