{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:00:05Z","timestamp":1791190805624,"version":"4.1.0"},"reference-count":21,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2001,2,6]]},"abstract":"<jats:p>\n            <jats:italic>Background<\/jats:italic>\n            \u2014Left ventricular failure is commonly preceded by a period of hypertrophy. Intriguingly, many of the signaling pathways that have been implicated in the regulation of hypertrophy, including the 3 mitogen-activated protein kinases (MAPKs: extracellular signal-regulated kinase, stress-activated protein kinase, and p38), protein phosphatase, calcineurin, and the protein kinase Akt and its target glycogen synthase kinase-3 (GSK-3), also regulate the apoptotic response.\n          <\/jats:p>\n          <jats:p>\n            <jats:italic>Methods and Results<\/jats:italic>\n            \u2014To understand the mechanisms that might regulate the progression of heart failure, we analyzed the activity of these signaling pathways in the hearts of patients with advanced heart failure, patients with compensated cardiac hypertrophy, and normal subjects. In patients with hypertrophy, neither the MAPK nor the Akt\/GSK-3 pathways were activated, and the dominant signaling pathway was calcineurin. In failing hearts, calcineurin activity was increased but less so than in the hypertrophied hearts, and all 3 MAPKs and Akt were activated (and, accordingly, GSK-3\u03b2 was inhibited), irrespective of whether the underlying diagnosis was ischemic or idiopathic cardiomyopathy.\n          <\/jats:p>\n          <jats:p>\n            <jats:italic>Conclusions<\/jats:italic>\n            \u2014In the failing heart, there is a clear prohypertrophic activity profile, likely occurring in response to increased systolic wall stress and neurohormonal mediators. However, with the activation of these hypertrophic pathways, potent proapoptotic and antiapoptotic signals may also be generated. Therapies directed at altering the balance of activity of these signaling pathways could potentially alter the progression of heart failure.\n          <\/jats:p>","DOI":"10.1161\/01.cir.103.5.670","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:09:32Z","timestamp":1339459772000},"page":"670-677","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":332,"title":["Differential Activation of Signal Transduction Pathways in Human Hearts With Hypertrophy Versus Advanced Heart Failure"],"prefix":"10.1161","volume":"103","author":[{"given":"Syed","family":"Haq","sequence":"first","affiliation":[{"name":"From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children\u2019s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Choukroun","sequence":"additional","affiliation":[{"name":"From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children\u2019s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae","family":"Lim","sequence":"additional","affiliation":[{"name":"From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children\u2019s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin M.","family":"Tymitz","sequence":"additional","affiliation":[{"name":"From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children\u2019s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"del Monte","sequence":"additional","affiliation":[{"name":"From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children\u2019s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Gwathmey","sequence":"additional","affiliation":[{"name":"From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children\u2019s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luanda","family":"Grazette","sequence":"additional","affiliation":[{"name":"From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children\u2019s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashour","family":"Michael","sequence":"additional","affiliation":[{"name":"From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children\u2019s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Hajjar","sequence":"additional","affiliation":[{"name":"From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children\u2019s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Force","sequence":"additional","affiliation":[{"name":"From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children\u2019s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"From the Cardiology (S.H., F.d.M., L.G., A.M., R.H., T.F.) and Renal Units (G.C.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Division of Molecular Cardiovascular Biology, Children\u2019s Hospital and University of Cincinnati, Cincinnati, Ohio (H.L., K.M.T., J.D.M.); and Boston University School of Medicine, Boston, Mass (J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.84.6.623"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.84.6.633"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.99.3.384"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.1999.0979"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/6430"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/71478"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.14.8144"},{"key":"e_1_3_2_8_2","first-page":"2906","volume":"13","year":"1999","unstructured":"Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999;13:2906\u20132927.","journal-title":"Genes Dev"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.100.23.2373"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5412.339"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.32.19929"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.950180708"},{"key":"e_1_3_2_13_2","doi-asserted-by":"crossref","unstructured":"Haq S Choukroun G Kang ZB et al. Glycogen synthase kinase-3\u03b2 is a negative regulator of cardiomyocyte hypertrophy. J Cell Biol.2000;151:117\u2013129.","DOI":"10.1083\/jcb.151.1.117"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6350"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.101.20.2431"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80043-4"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81573-1"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.6.4008"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/23060"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.14.5227-5234.2000"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M000870200"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/01.CIR.103.5.670","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T13:08:05Z","timestamp":1715519285000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/01.CIR.103.5.670"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,2,6]]},"references-count":21,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2001,2,6]]}},"alternative-id":["10.1161\/01.CIR.103.5.670"],"URL":"https:\/\/doi.org\/10.1161\/01.cir.103.5.670","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,2,6]]},"assertion":[{"value":"2000-07-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-10-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2001-02-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}