{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T14:21:17Z","timestamp":1773152477042,"version":"3.50.1"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[1999,2,16]]},"abstract":"<jats:p>\n            <jats:italic>Background<\/jats:italic>\n            \u2014The mechanisms through which NOS2-mediated pathways regulate graft failure in acute cardiac rejection are ill defined. To determine whether apoptosis promoted by NOS2 may contribute, we used a heterotopic transplant model to study mouse cardiac allografts placed in recipients with targeted gene deletion of NOS2.\n          <\/jats:p>\n          <jats:p>\n            <jats:italic>Methods and Results<\/jats:italic>\n            \u2014Using 5 different indexes of apoptosis, we showed that mouse cardiac allografts placed in NOS2 \u2212\/\u2212 recipients (n=7) had reduced apoptotic activity compared with those in NOS2 +\/+ controls (n=8). There were significantly fewer TUNEL-positive nuclei per high-powered field (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.01), less DNA fragmentation (antinucleosome ELISA;\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05), lower corrected transcript levels for caspase-1 and -3 (\n            <jats:sup>32<\/jats:sup>\n            P reverse transcriptase\u2013polymerase chain reaction;\n            <jats:italic>P<\/jats:italic>\n            &lt;0.01), and reduced caspase-3 activity (cleavage of DEVD-pNA [\n            <jats:italic>P<\/jats:italic>\n            &lt;0.001] and poly [ADP-ribose] polymerase) in grafts from NOS2 \u2212\/\u2212 recipients. This concordant reduction in apoptotic indexes paralleled the improved histological outcome of grafts transplanted into NOS2 \u2212\/\u2212 recipients (assessed as rejection scores;\n            <jats:italic>P<\/jats:italic>\n            =0.012). To identify pathways controlled by NOS2, we compared intragraft transcript levels of potential triggers and regulators. Whereas Fas ligand\/Fas and tumor necrosis factor (TNF)-\u03b1\/TNF receptor-1 levels were not altered by NOS2 deficiency, transcript levels for p53 were significantly lower in grafts from NOS2 \u2212\/\u2212 recipients, coinciding with a significant increase in the antiapoptotic Bcl-2\/Bax balance and decrease in Bcl-X\n            <jats:sub>l<\/jats:sub>\n            levels.\n          <\/jats:p>\n          <jats:p>\n            <jats:italic>Conclusions<\/jats:italic>\n            \u2014Using NOS2 knockout mice, we demonstrated that NOS2-mediated pathways can promote acute rejection, at least in part, by inducing apoptotic cell death. When NOS2 is present, p53 might control NOS2-mediated apoptosis by stimulating Bax and repressing Bcl-2 and Bcl-X\n            <jats:sub>l<\/jats:sub>\n            expression, which may activate the cell death program in the rejecting heart.\n          <\/jats:p>","DOI":"10.1161\/01.cir.99.6.836","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:42:29Z","timestamp":1339461749000},"page":"836-842","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":76,"title":["Attenuated Acute Cardiac Rejection in NOS2 \u2212\/\u2212 Recipients Correlates With Reduced Apoptosis"],"prefix":"10.1161","volume":"99","author":[{"given":"Jo\u0308rg","family":"Koglin","sequence":"first","affiliation":[{"name":"From the Cardiovascular Biology Laboratory, Harvard School of Public Health (J.K., T.G.-J., M.E.R.), Brigham and Women\u2019s Hospital (M.E.R.), and Harvard Medical School (M.E.R.), Boston, Mass; Cardiovascular Research Laboratories, Department of Pathology and Laboratory Medicine, St Paul\u2019s Hospital, University of British Columbia (D.J.G., C.M.C., B.M.M.), and QLT Phototherapeutics Inc (D.J.G., C.M.C.), Vancouver, British Colombia, Canada; and Merck Research Laboratories (J.S.M.), Rahway, NJ."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Granville","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Biology Laboratory, Harvard School of Public Health (J.K., T.G.-J., M.E.R.), Brigham and Women\u2019s Hospital (M.E.R.), and Harvard Medical School (M.E.R.), Boston, Mass; Cardiovascular Research Laboratories, Department of Pathology and Laboratory Medicine, St Paul\u2019s Hospital, University of British Columbia (D.J.G., C.M.C., B.M.M.), and QLT Phototherapeutics Inc (D.J.G., C.M.C.), Vancouver, British Colombia, Canada; and Merck Research Laboratories (J.S.M.), Rahway, NJ."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Troels","family":"Glysing-Jensen","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Biology Laboratory, Harvard School of Public Health (J.K., T.G.-J., M.E.R.), Brigham and Women\u2019s Hospital (M.E.R.), and Harvard Medical School (M.E.R.), Boston, Mass; Cardiovascular Research Laboratories, Department of Pathology and Laboratory Medicine, St Paul\u2019s Hospital, University of British Columbia (D.J.G., C.M.C., B.M.M.), and QLT Phototherapeutics Inc (D.J.G., C.M.C.), Vancouver, British Colombia, Canada; and Merck Research Laboratories (J.S.M.), Rahway, NJ."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John S.","family":"Mudgett","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Biology Laboratory, Harvard School of Public Health (J.K., T.G.-J., M.E.R.), Brigham and Women\u2019s Hospital (M.E.R.), and Harvard Medical School (M.E.R.), Boston, Mass; Cardiovascular Research Laboratories, Department of Pathology and Laboratory Medicine, St Paul\u2019s Hospital, University of British Columbia (D.J.G., C.M.C., B.M.M.), and QLT Phototherapeutics Inc (D.J.G., C.M.C.), Vancouver, British Colombia, Canada; and Merck Research Laboratories (J.S.M.), Rahway, NJ."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris M.","family":"Carthy","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Biology Laboratory, Harvard School of Public Health (J.K., T.G.-J., M.E.R.), Brigham and Women\u2019s Hospital (M.E.R.), and Harvard Medical School (M.E.R.), Boston, Mass; Cardiovascular Research Laboratories, Department of Pathology and Laboratory Medicine, St Paul\u2019s Hospital, University of British Columbia (D.J.G., C.M.C., B.M.M.), and QLT Phototherapeutics Inc (D.J.G., C.M.C.), Vancouver, British Colombia, Canada; and Merck Research Laboratories (J.S.M.), Rahway, NJ."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce M.","family":"McManus","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Biology Laboratory, Harvard School of Public Health (J.K., T.G.-J., M.E.R.), Brigham and Women\u2019s Hospital (M.E.R.), and Harvard Medical School (M.E.R.), Boston, Mass; Cardiovascular Research Laboratories, Department of Pathology and Laboratory Medicine, St Paul\u2019s Hospital, University of British Columbia (D.J.G., C.M.C., B.M.M.), and QLT Phototherapeutics Inc (D.J.G., C.M.C.), Vancouver, British Colombia, Canada; and Merck Research Laboratories (J.S.M.), Rahway, NJ."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary E.","family":"Russell","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Biology Laboratory, Harvard School of Public Health (J.K., T.G.-J., M.E.R.), Brigham and Women\u2019s Hospital (M.E.R.), and Harvard Medical School (M.E.R.), Boston, Mass; Cardiovascular Research Laboratories, Department of Pathology and Laboratory Medicine, St Paul\u2019s Hospital, University of British Columbia (D.J.G., C.M.C., B.M.M.), and QLT Phototherapeutics Inc (D.J.G., C.M.C.), Vancouver, British Colombia, Canada; and Merck Research Laboratories (J.S.M.), Rahway, NJ."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0033-0620(05)80001-5"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.150.11.5080"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.5.1753"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.27.3.823"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(94)01161-3"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.6.2442"},{"key":"e_1_3_2_7_2","first-page":"1799","volume":"9","year":"1994","unstructured":"Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC. 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