{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:51:44Z","timestamp":1793314304087,"version":"4.5.0"},"reference-count":51,"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":[[2009,8,14]]},"abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic>Rationale:<\/jats:italic>\n                    <\/jats:bold>\n                    Pathological cardiac myocyte hypertrophy is thought to be induced by the persistent increases in intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    needed to maintain cardiac function when systolic wall stress is increased. Hypertrophic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    binds to calmodulin (CaM) and activates the phosphatase calcineurin (Cn) and CaM kinase (CaMK)II. Cn dephosphorylates cytoplasmic NFAT (nuclear factor of activated T cells), inducing its translocation to the nucleus where it activates antiapoptotic and hypertrophic target genes. Cytoplasmic CaMKII regulates Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling proteins but whether or not it is directly involved in hypertrophic and survival signaling is not known.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>\n                      <jats:italic>Objective:<\/jats:italic>\n                    <\/jats:bold>\n                    This study explored the hypothesis that cytoplasmic CaMKII reduces NFAT nuclear translocation by inhibiting the phosphatase activity of Cn.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>\n                      <jats:italic>Methods and Results:<\/jats:italic>\n                    <\/jats:bold>\n                    Green fluorescent protein\u2013tagged NFATc3 was used to determine the cellular location of NFAT in cultured neonatal rat ventricular myocytes (NRVMs) and adult feline ventricular myocytes. Constitutively active (CaMKII-CA) or dominant negative (CaMKII-DN) mutants of cytoplasmic targeted CaMKII\n                    <jats:sub>\u03b4c<\/jats:sub>\n                    were used to activate and inhibit cytoplasmic CaMKII activity. In NRVM CaMKII-DN (48.5\u00b13%,\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.01 versus control) increased, whereas CaMKII-CA decreased (5.9\u00b11%,\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.01 versus control) NFAT nuclear translocation (Control: 12.3\u00b11%). Cn inhibitors were used to show that these effects were caused by modulation of Cn activity. Increasing Ca\n                    <jats:sup>2+<\/jats:sup>\n                    increased Cn-dependent NFAT translocation (to 71.7\u00b17%,\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.01) and CaMKII-CA reduced this effect (to 17.6\u00b14%). CaMKII-CA increased TUNEL and caspase-3 activity (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.05). CaMKII directly phosphorylated Cn at Ser197 in CaMKII-CA infected NRVMs and in hypertrophied feline hearts.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>\n                      <jats:italic>Conclusion:<\/jats:italic>\n                    <\/jats:bold>\n                    These data show that activation of cytoplasmic CaMKII inhibits NFAT nuclear translocation by phosphorylation and subsequent inhibition of Cn.\n                  <\/jats:p>","DOI":"10.1161\/circresaha.109.194035","type":"journal-article","created":{"date-parts":[[2009,7,16]],"date-time":"2009-07-16T22:07:39Z","timestamp":1247782059000},"page":"316-325","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":138,"title":["CaMKII Negatively Regulates Calcineurin\u2013NFAT Signaling in Cardiac Myocytes"],"prefix":"10.1161","volume":"105","author":[{"given":"Scott M.","family":"MacDonnell","sequence":"first","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jutta","family":"Weisser-Thomas","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Kubo","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Hanscome","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghang","family":"Liu","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naser","family":"Jaleel","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remus","family":"Berretta","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongwen","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan H.","family":"Brown","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdel-Karim","family":"Sabri","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven R.","family":"Houser","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (S.M.M., J.W.-T., H.K., M.H., N.J., R.B., X.C., A.-K.S., S.R.H.), Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa; Cincinnati Children\u2019s Hospital Medical Center (Q.L., J.D.M.), Ohio; and Department of Pharmacology (J.H.B.), University of California at San Diego, La Jolla."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"e_1_3_3_2_2","first-page":"589","volume":"7","year":"2006","unstructured":"Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev. 2006; 7: 589\u2013600.","journal-title":"Nat Rev"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81573-1"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2002.2038"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.87.9.731"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.104.1.97"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000120390.68287.bb"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.07.121"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00661-2"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.101.24.2863"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejheart.2003.07.007"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.86.3.255"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000069211.82346.46"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00546.2002"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000069686.31472.c5"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.644583"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200316326"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.04.026"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2008.01295.x"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-4889(94)90221-6"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00788498"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.49.31203"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707083200"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.84.6.713"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38022"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.75.5.7923631"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M611507200"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1215"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.181.3.1217"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.16.2499"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1998.275.2.H577"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.51.6.6216022"},{"key":"e_1_3_3_33_2","first-page":"H2009","volume":"265","year":"1993","unstructured":"Bailey BA, Houser SR. Sarcoplasmic reticulum-related changes in cytosolic calcium in pressure-overload-induced feline LV hypertrophy. Am J Physiol. 1993; 265: H2009\u2013H2016.","journal-title":"Am J Physiol"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000158966.58380.37"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.104.505784"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2828(92)93191-L"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.231619298"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.103.5.670"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.26.10.3785-3797.2006"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.18.7001"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)84738-5"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00450a002"},{"key":"e_1_3_3_43_2","doi-asserted-by":"crossref","unstructured":"Bers DM. Excitation-Contraction Coupling and Cardiac Contractile Force. 2nd ed. Dordrecht The Netherlands: Kluwer Academic Publishers; 2001.","DOI":"10.1007\/978-94-010-0658-3"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/0143-4160(87)90002-9"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1050-1738(00)00057-8"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.63.1.391"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1985.tb05504.x"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.05.182"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.26.1.78"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.27.17223"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00353.2006"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.109.194035","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T00:04:37Z","timestamp":1715558677000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.109.194035"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,8,14]]},"references-count":51,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2009,8,14]]}},"alternative-id":["10.1161\/CIRCRESAHA.109.194035"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.109.194035","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1164636.626433","asserted-by":"object"}]},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,8,14]]},"assertion":[{"value":"2009-07-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}