{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:37:31Z","timestamp":1791337051757,"version":"4.3.1"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2000,3,31]]},"abstract":"<jats:p>\n            <jats:italic>Abstract<\/jats:italic>\n            \u2014Three major mammalian mitogen-activated protein kinases, extracellular signal\u2013regulated kinase (ERK), p38, and c-Jun NH\n            <jats:sub>2<\/jats:sub>\n            -terminal protein kinase (JNK), have been identified in the cardiomyocyte, but their respective roles in the heart are not well understood. The present study explored their functions and cross talk in ischemia\/reoxygenation (I\/R)\u2013induced cardiac apoptosis. Exposing rat neonatal cardiomyocytes to ischemia resulted in a rapid and transient activation of ERK, p38, and JNK. On reoxygenation, further activation of all 3 mitogen-activated protein kinases was noted; peak activities increased (fold) by 5.5, 5.2, and 6.2, respectively. Visual inspection of myocytes exposed to I\/R identified 18.6% of the cells as showing morphological features of apoptosis, which was further confirmed by DNA ladder and terminal deoxyribonucleotide transferase\u2013mediated dUTP nick end labeling (TUNEL). Myocytes treated with PD98059, a MAPK\/ERK kinase (MEK1\/MEK2) inhibitor, displayed a suppression of I\/R-induced ERK activation, whereas p38 and JNK activities were increased by 70.3% and 55.0%, respectively. In addition, the number of apoptotic cells was increased to 33.4%. With pretreatment of cells with SB242719, a selective p38 inhibitor, or SB203580, a p38 and JNK2 inhibitor, I\/R+PD98059-induced apoptotic cells were reduced by 42.8% and 63.3%, respectively. Hearts isolated from rats treated with PD98059 and subjected to global ischemia (30 minutes)\/reoxygenation (1 hour) showed a diminished functional recovery compared with the vehicle group. Coadministration of SB203580 attenuated the detrimental effects of PD98059 and significantly improved cardiac functional recovery. The data taken together suggest that ERK plays a protective role, whereas p38 and JNK mediate apoptosis in cardiomyocytes subjected to I\/R, and the dynamic balance of their activities is critical in determining cardiomyocyte fate subsequent to reperfusional injury.\n          <\/jats:p>","DOI":"10.1161\/01.res.86.6.692","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:52:16Z","timestamp":1339462336000},"page":"692-699","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":317,"title":["Inhibition of Extracellular Signal\u2013Regulated Kinase Enhances Ischemia\/Reoxygenation\u2013Induced Apoptosis in Cultured Cardiac Myocytes and Exaggerates Reperfusion Injury in Isolated Perfused Heart"],"prefix":"10.1161","volume":"86","author":[{"given":"Tian-Li","family":"Yue","sequence":"first","affiliation":[{"name":"From the Departments of Cardiovascular Pharmacology (T-L.Y., C.W., J-L.G., G.Z F., E.H.O.), Bone and Cartilage (S.K., J.C.L.), and Experimental Toxicology (H.T., B.M.), SmithKline Beecham Pharmaceuticals, King of Prussia, and Division of Emergency Medicine (X-L.M.), Thomas Jefferson University, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanlin","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Departments of Cardiovascular Pharmacology (T-L.Y., C.W., J-L.G., G.Z F., E.H.O.), Bone and Cartilage (S.K., J.C.L.), and Experimental Toxicology (H.T., B.M.), SmithKline Beecham Pharmaceuticals, King of Prussia, and Division of Emergency Medicine (X-L.M.), Thomas Jefferson University, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan-Li","family":"Gu","sequence":"additional","affiliation":[{"name":"From the Departments of Cardiovascular Pharmacology (T-L.Y., C.W., J-L.G., G.Z F., E.H.O.), Bone and Cartilage (S.K., J.C.L.), and Experimental Toxicology (H.T., B.M.), SmithKline Beecham Pharmaceuticals, King of Prussia, and Division of Emergency Medicine (X-L.M.), Thomas Jefferson University, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Ling","family":"Ma","sequence":"additional","affiliation":[{"name":"From the Departments of Cardiovascular Pharmacology (T-L.Y., C.W., J-L.G., G.Z F., E.H.O.), Bone and Cartilage (S.K., J.C.L.), and Experimental Toxicology (H.T., B.M.), SmithKline Beecham Pharmaceuticals, King of Prussia, and Division of Emergency Medicine (X-L.M.), Thomas Jefferson University, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Kumar","sequence":"additional","affiliation":[{"name":"From the Departments of Cardiovascular Pharmacology (T-L.Y., C.W., J-L.G., G.Z F., E.H.O.), Bone and Cartilage (S.K., J.C.L.), and Experimental Toxicology (H.T., B.M.), SmithKline Beecham Pharmaceuticals, King of Prussia, and Division of Emergency Medicine (X-L.M.), Thomas Jefferson University, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Lee","sequence":"additional","affiliation":[{"name":"From the Departments of Cardiovascular Pharmacology (T-L.Y., C.W., J-L.G., G.Z F., E.H.O.), Bone and Cartilage (S.K., J.C.L.), and Experimental Toxicology (H.T., B.M.), SmithKline Beecham Pharmaceuticals, King of Prussia, and Division of Emergency Medicine (X-L.M.), Thomas Jefferson University, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giora Z.","family":"Feuerstein","sequence":"additional","affiliation":[{"name":"From the Departments of Cardiovascular Pharmacology (T-L.Y., C.W., J-L.G., G.Z F., E.H.O.), Bone and Cartilage (S.K., J.C.L.), and Experimental Toxicology (H.T., B.M.), SmithKline Beecham Pharmaceuticals, King of Prussia, and Division of Emergency Medicine (X-L.M.), Thomas Jefferson University, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heath","family":"Thomas","sequence":"additional","affiliation":[{"name":"From the Departments of Cardiovascular Pharmacology (T-L.Y., C.W., J-L.G., G.Z F., E.H.O.), Bone and Cartilage (S.K., J.C.L.), and Experimental Toxicology (H.T., B.M.), SmithKline Beecham Pharmaceuticals, King of Prussia, and Division of Emergency Medicine (X-L.M.), Thomas Jefferson University, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly","family":"Maleeff","sequence":"additional","affiliation":[{"name":"From the Departments of Cardiovascular Pharmacology (T-L.Y., C.W., J-L.G., G.Z F., E.H.O.), Bone and Cartilage (S.K., J.C.L.), and Experimental Toxicology (H.T., B.M.), SmithKline Beecham Pharmaceuticals, King of Prussia, and Division of Emergency Medicine (X-L.M.), Thomas Jefferson University, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliot H.","family":"Ohlstein","sequence":"additional","affiliation":[{"name":"From the Departments of Cardiovascular Pharmacology (T-L.Y., C.W., J-L.G., G.Z F., E.H.O.), Bone and Cartilage (S.K., J.C.L.), and Experimental Toxicology (H.T., B.M.), SmithKline Beecham Pharmaceuticals, King of Prussia, and Division of Emergency Medicine (X-L.M.), Thomas Jefferson University, Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(97)80061-0"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(98)80143-9"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90133-3"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8052857"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.15.4404"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81375-6"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.26.16415"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.78.6.947"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(96)00191-X"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.83.4.345"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.10.6272"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.14.8232"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.10.5423"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.4.2161"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119709"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.17.7686"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.46.27489"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)00324-X"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1996.0016"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.13.7228"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.1997.0614"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.3.1479"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.82.2.166"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(97)00179-X"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.99.13.1685"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.24.14560"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.1.154"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.20.11975"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.51.30823"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.79.2.162"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(97)00388-2"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/01.RES.86.6.692","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T20:46:06Z","timestamp":1715546766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/01.RES.86.6.692"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,3,31]]},"references-count":31,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2000,3,31]]}},"alternative-id":["10.1161\/01.RES.86.6.692"],"URL":"https:\/\/doi.org\/10.1161\/01.res.86.6.692","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,3,31]]},"assertion":[{"value":"1999-12-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-01-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-03-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}