{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T22:13:56Z","timestamp":1791152036926,"version":"4.1.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2013,11,19]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Long-term inhibition of nitric oxide synthase by L-arginine analogues such as N\n              <jats:sup>\u03c9<\/jats:sup>\n              -nitro-\n              <jats:sc>l<\/jats:sc>\n              -arginine methyl ester (L-NAME) has been shown to induce senescence in vitro and systemic hypertension and arteriosclerosis in vivo. We previously reported that plasminogen activator inhibitor-1 (PAI-1)\u2013deficient mice (PAI-1\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              ) are protected against L-NAME-induced pathologies. In this study, we investigated whether a novel, orally active PAI-1 antagonist (TM5441) has a similar protective effect against L-NAME treatment. Additionally, we studied whether L-NAME can induce vascular senescence in vivo and investigated the role of PAI-1 in this process.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Wild-type mice received either L-NAME or L-NAME and TM5441 for 8 weeks. Systolic blood pressure was measured every 2 weeks. We found that TM5441 attenuated the development of hypertension and cardiac hypertrophy compared with animals that had received L-NAME alone. Additionally, TM5441-treated mice had a 34% reduction in periaortic fibrosis relative to animals on L-NAME alone. Finally, we investigated the development of vascular senescence by measuring p16\n              <jats:sup>Ink4a<\/jats:sup>\n              expression and telomere length in aortic tissue. We found that L-NAME increased p16\n              <jats:sup>Ink4a<\/jats:sup>\n              expression levels and decreased telomere length, both of which were prevented with TM5441 cotreatment.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Pharmacological inhibition of PAI-1 is protective against the development of hypertension, cardiac hypertrophy, and periaortic fibrosis in mice treated with L-NAME. Furthermore, PAI-1 inhibition attenuates the arterial expression of p16\n              <jats:sup>Ink4a<\/jats:sup>\n              and maintains telomere length. PAI-1 appears to play a pivotal role in vascular senescence, and these findings suggest that PAI-1 antagonists may provide a novel approach in preventing vascular aging and hypertension.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.113.003192","type":"journal-article","created":{"date-parts":[[2013,10,4]],"date-time":"2013-10-04T03:26:20Z","timestamp":1380857180000},"page":"2318-2324","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":122,"title":["Plasminogen Activator Inhibitor-1 Antagonist TM5441 Attenuates N\n            <sup>\u03c9<\/sup>\n            -Nitro-\n            <scp>l<\/scp>\n            -Arginine Methyl Ester\u2013Induced Hypertension and Vascular Senescence"],"prefix":"10.1161","volume":"128","author":[{"given":"Amanda E.","family":"Boe","sequence":"first","affiliation":[{"name":"From the Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mesut","family":"Eren","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila B.","family":"Murphy","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine E.","family":"Kamide","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuhiko","family":"Ichimura","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Terry","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"McAnally","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Layton H.","family":"Smith","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Miyata","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas E.","family":"Vaughan","sequence":"additional","affiliation":[{"name":"From the Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2980249"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3109\/07853890.2011.585658"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/377239a0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.23.13176"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.32.6.958"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115849"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.20.3.298"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.18.11.1771"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.1999.1053"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01062709"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/383441a0"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/13459"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118201"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1997.20"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000023186.60090.fb"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/hc3301.092803"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2002.2001"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2009.272"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.107.157479"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1993.2153"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/hh2101.098443"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607873103"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2010.03.013"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2560"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1448"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1120437109"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/atvbaha.107.157479"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2009.272"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/30.10.e47"},{"key":"e_1_3_4_31_2","first-page":"17","article-title":"Real-time PCR assay for measurement of mouse telomeres.","volume":"56","author":"Callicott RJ","year":"2006","unstructured":"Callicott RJ, Womack JE. 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