{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:26:58Z","timestamp":1791300418533,"version":"4.1.0"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2013,10]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>In aortic aneurysms the arterial vessel wall is dilated because of destruction of its integrity, which may lead to lethal vessel rupture. Chronic infiltration of inflammatory cells into the vessel wall is fundamental to aneurysm pathology. We aim to limit aneurysm growth by inhibition of inflammation and reducing endothelial cell (EC) activation with immunosuppressive drug azathioprine (Aza).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>Aza and its metabolite 6-mercaptopurine have anti-inflammatory effects on leukocytes. We here demonstrate that treatment of ECs with 6-mercaptopurine inhibits cell activation as illustrated by reduced expression of interleukin-12, CCL5, CCL2, and vascular cell adhesion molecule-1 and inhibition of monocyte\u2013EC adhesion. The underlying mechanism of 6-mercaptopurine involves suppression of GTPase Rac1 activation, resulting in reduced phosphorylation of c-Jun-terminal-N-kinase and c-Jun. Subsequently, the effect of Aza was investigated in aneurysm formation in the angiotensin II aneurysm mouse model in apolipoprotein E\u2013deficient mice. We demonstrated that Aza decreases de novo aortic aneurysm formation from an average aneurysm severity score of 2.1 (control group) to 0.6 (Aza group), and that Aza effectively delays aorta pathology in a progression experiment, resulting in a reduced severity score from 2.8 to 1.7 in Aza-treated mice. In line with the in vitro observations, Aza-treated mice showed less c-Jun-terminal-N-kinase activation in ECs and reduced leukocyte influx in the aortic wall.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>The immunosuppressive drug Aza has an anti-inflammatory effect and in ECs inhibits Rac1 and c-Jun-terminal-N-kinase activation, which may explain the protective effect of Aza in aneurysm development and, most importantly for clinical implications, aneurysm severity.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.113.301394","type":"journal-article","created":{"date-parts":[[2013,8,16]],"date-time":"2013-08-16T02:44:59Z","timestamp":1376621099000},"page":"2380-2388","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":38,"title":["Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells"],"prefix":"10.1161","volume":"33","author":[{"given":"Goran","family":"Marinkovi\u0107","sequence":"first","affiliation":[{"name":"From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijntje","family":"Hibender","sequence":"additional","affiliation":[{"name":"From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Hoogenboezem","sequence":"additional","affiliation":[{"name":"From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"van Broekhoven","sequence":"additional","affiliation":[{"name":"From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arginell F.","family":"Girigorie","sequence":"additional","affiliation":[{"name":"From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natascha","family":"Bleeker","sequence":"additional","affiliation":[{"name":"From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anouk A.J.","family":"Hamers","sequence":"additional","affiliation":[{"name":"From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Stap","sequence":"additional","affiliation":[{"name":"From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaap D.","family":"van Buul","sequence":"additional","affiliation":[{"name":"From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlie J.M.","family":"de Vries","sequence":"additional","affiliation":[{"name":"From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"de Waard","sequence":"additional","affiliation":[{"name":"From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.111.030379"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001895"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69250-7"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.108.806505"},{"key":"e_1_3_4_6_2","first-page":"CD009536","article-title":"Medical treatment for small abdominal aortic aneurysms.","volume":"9","author":"Rughani G","year":"2012","unstructured":"Rughani G, Robertson L, Clarke M. Medical treatment for small abdominal aortic aneurysms. Cochrane Database Syst Rev. 2012;9:CD009536.","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2010.02.264"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejvs.2012.06.021"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000214999.12921.4f"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2010.01.042"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.110.221499"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-10-298"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000216119.79008.ac"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2004.05.020"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110503"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.1990.01410180025004"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.008573"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210149"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60324-9"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq028"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.050932"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.626838"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.110.205674"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI16432"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1335"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.1.640"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1159\/000345525"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000254680.71485.92"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2006.04.047"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000085631.76095.64"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.112.00009"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)61453-5"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nut.2012.02.006"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2012.07.034"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1227\/00006123-200210000-00027"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.107.497875"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2011.11.1024"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.111.036061"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2011.07.053"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.112.300329"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keq416"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2004.08.014"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1744-313X.2009.00845.x"},{"key":"e_1_3_4_44_2","first-page":"CD000067","article-title":"Azathioprine for maintaining remission of Crohn\u2019s disease.","author":"Pearson DC","year":"2000","unstructured":"Pearson DC, May GR, Fick G, Sutherland LR. Azathioprine for maintaining remission of Crohn\u2019s disease. Cochrane Database Syst Rev 2000:CD000067.","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_3_4_45_2","first-page":"CD000545","article-title":"Azathioprine or 6-mercaptopurine for inducing remission of Crohn\u2019s disease.","author":"Sandborn W","year":"2000","unstructured":"Sandborn W, Sutherland L, Pearson D, May G, Modigliani R, Prantera C. Azathioprine or 6-mercaptopurine for inducing remission of Crohn\u2019s disease. Cochrane Database Syst Rev 2000:CD000545.","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_3_4_46_2","first-page":"CD000478","article-title":"Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis.","author":"Timmer A","year":"2007","unstructured":"Timmer A, McDonald JW, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2007:CD000478.","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.68.1.459"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.174367"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000058404.92759.32"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI8931"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2007.09.016"},{"key":"e_1_3_4_52_2","first-page":"234","volume-title":"Vascular and Endovascular Challenges","author":"Meijer CA","year":"2013","unstructured":"Meijer CA, van Bockel JH, Lindeman JH. Doxycycline to inhibit abdominal aortic aneurysm progression. In: , Greenhalgh RM, ed. Vascular and Endovascular Challenges. London: Biba; 2013:234\u2013242."},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0046411"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.113.301394","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T23:05:02Z","timestamp":1715555102000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.113.301394"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,10]]},"references-count":52,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2013,10]]}},"alternative-id":["10.1161\/ATVBAHA.113.301394"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.113.301394","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,10]]},"assertion":[{"value":"2013-02-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-07-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-08-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}