{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T01:57:43Z","timestamp":1792634263017,"version":"4.5.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2013,8,2]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Growing evidence indicates that oxidative stress contributes markedly to endothelial dysfunction. The selenoenzyme glutathione peroxidase 4 (Gpx4) is an intracellular antioxidant enzyme important for the protection of membranes by its unique activity to reduce complex hydroperoxides in membrane bilayers and lipoprotein particles. Yet a role of Gpx4 in endothelial cell function has remained enigmatic.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>To investigate the role of Gpx4 ablation and subsequent lipid peroxidation in the vascular compartment in vivo.<\/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>Endothelium-specific deletion of Gpx4 had no obvious impact on normal vascular homeostasis, nor did it impair tumor-derived angiogenesis in mice maintained on a normal diet. In stark contrast, aortic explants from endothelium-specific Gpx4 knockout mice showed a markedly reduced number of endothelial branches in sprouting assays. To shed light onto this apparent discrepancy between the in vivo and ex vivo results, we depleted mice of a second antioxidant, vitamin E, which is normally absent under ex vivo conditions. Therefore, mice were fed a vitamin E\u2013depleted diet for 6 weeks before endothelial deletion of Gpx4 was induced by 4-hydroxytamoxifen. Surprisingly, \u224880% of the knockout mice died. Histopathological analysis revealed detachment of endothelial cells from the basement membrane and endothelial cell death in multiple organs, which triggered thrombus formation. Thromboembolic events were the likely cause of various clinical pathologies, including heart failure, renal and splenic microinfarctions, and paraplegia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Here, we show for the first time that in the absence of Gpx4, sufficient vitamin E supplementation is crucial for endothelial viability.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.113.279984","type":"journal-article","created":{"date-parts":[[2013,6,15]],"date-time":"2013-06-15T00:21:01Z","timestamp":1371255661000},"page":"408-417","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":157,"title":["Combined Deficiency in Glutathione Peroxidase 4 and Vitamin E Causes Multiorgan Thrombus Formation and Early Death in Mice"],"prefix":"10.1161","volume":"113","author":[{"given":"Markus","family":"Wortmann","sequence":"first","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Schneider","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Pircher","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Hellfritsch","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Aichler","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naidu","family":"Vegi","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pirkko","family":"K\u00f6lle","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kuhlencordt","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Walch","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Pohl","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg W.","family":"Bornkamm","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Conrad","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Beck","sequence":"additional","affiliation":[{"name":"From the Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany (M.W., M.S., J.P., J.H., U.P., H.B.); Institute for Stroke and Dementia Research, University of Munich Medical Center, Munich, Germany (M.S.); Research Unit Analytical Pathology, Institute of Pathology (M.A., A.W.), and Institute for Developmental Genetics (M.C.), German Research Center for Environmental Health, Helmholtz..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.bmb.a072631"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1999.tb09231.x"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(02)01197-8"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.3109\/10715769109145777"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)40252-4"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1994.1105"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(02)01360-6"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(03)00734-4"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.07.005"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1593\/neo.91782"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2003.08.008"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)40739-4"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1993.264.3.C715"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9150(99)00486-4"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2007.09.009"},{"key":"e_1_3_5_17_2","first-page":"163","article-title":"Determinants of PHGPx expression in a cultured endothelial cell line.","volume":"10","author":"Brigelius-Floh\u00e9 R","year":"1997","unstructured":"Brigelius-Floh\u00e9 R, Friedrichs B, Maurer S, Streicher R. 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