{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:17:14Z","timestamp":1792621034679,"version":"4.5.0"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2007,11,26]]},"abstract":"<jats:p>\n                    Glycogen synthase kinase (GSK)-3, a negative regulator of cardiac hypertrophy, is inactivated in failing hearts. To examine the histopathological and functional consequence of the persistent inhibition of GSK-3\u03b2 in the heart in vivo, we generated transgenic mice with cardiac-specific overexpression of dominant negative GSK-3\u03b2 (Tg-GSK-3\u03b2-DN) and tetracycline-regulatable wild-type GSK-3\u03b2. GSK-3\u03b2-DN significantly reduced the kinase activity of endogenous GSK-3\u03b2, inhibited phosphorylation of eukaryotic translation initiation factor 2B\u03b5, and induced accumulation of \u03b2-catenin and myeloid cell leukemia-1, confirming that GSK-3\u03b2-DN acts as a dominant negative in vivo. Tg-GSK-3\u03b2-DN exhibited concentric hypertrophy at baseline, accompanied by upregulation of the \u03b1-myosin heavy chain gene and increases in cardiac function, as evidenced by a significantly greater\n                    <jats:italic>E<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    after dobutamine infusion and percentage of contraction in isolated cardiac myocytes, indicating that inhibition of GSK-3\u03b2 induces well-compensated hypertrophy. Although transverse aortic constriction induced a similar increase in hypertrophy in both Tg-GSK-3\u03b2-DN and nontransgenic mice, Tg-GSK-3\u03b2-DN exhibited better left ventricular function and less fibrosis and apoptosis than nontransgenic mice. Induction of the GSK-3\u03b2 transgene in tetracycline-regulatable wild-type GSK-3\u03b2 mice induced left ventricular dysfunction and premature death, accompanied by increases in apoptosis and fibrosis. Overexpression of GSK-3\u03b2-DN in cardiac myocytes inhibited tumor necrosis factor-\u03b1\u2013induced apoptosis, and the antiapoptotic effect of GSK-3\u03b2-DN was abrogated in the absence of myeloid cell leukemia-1. These results suggest that persistent inhibition of GSK-3\u03b2 induces compensatory hypertrophy, inhibits apoptosis and fibrosis, and increases cardiac contractility and that the antiapoptotic effect of GSK-3\u03b2 inhibition is mediated by myeloid cell leukemia-1. Thus, downregulation of GSK-3\u03b2 during heart failure could be compensatory.\n                  <\/jats:p>","DOI":"10.1161\/circresaha.107.160614","type":"journal-article","created":{"date-parts":[[2007,9,27]],"date-time":"2007-09-27T21:01:16Z","timestamp":1190926876000},"page":"1164-1174","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":103,"title":["Inhibition of Glycogen Synthase Kinase 3\u03b2 During Heart Failure Is Protective"],"prefix":"10.1161","volume":"101","author":[{"given":"Shinichi","family":"Hirotani","sequence":"first","affiliation":[{"name":"From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine &amp; Dentistry of New Jersey, New Jersey Medical School, Newark; and Centro de Biologi\u0301a Molecular \u201cSevero Ochoa\u201d (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Auto\u0301noma de Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyong","family":"Zhai","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine &amp; Dentistry of New Jersey, New Jersey Medical School, Newark; and Centro de Biologi\u0301a Molecular \u201cSevero Ochoa\u201d (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Auto\u0301noma de Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideharu","family":"Tomita","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine &amp; Dentistry of New Jersey, New Jersey Medical School, Newark; and Centro de Biologi\u0301a Molecular \u201cSevero Ochoa\u201d (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Auto\u0301noma de Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Galeotti","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine &amp; Dentistry of New Jersey, New Jersey Medical School, Newark; and Centro de Biologi\u0301a Molecular \u201cSevero Ochoa\u201d (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Auto\u0301noma de Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Marquez","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine &amp; Dentistry of New Jersey, New Jersey Medical School, Newark; and Centro de Biologi\u0301a Molecular \u201cSevero Ochoa\u201d (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Auto\u0301noma de Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumin","family":"Gao","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine &amp; Dentistry of New Jersey, New Jersey Medical School, Newark; and Centro de Biologi\u0301a Molecular \u201cSevero Ochoa\u201d (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Auto\u0301noma de Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chull","family":"Hong","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine &amp; Dentistry of New Jersey, New Jersey Medical School, Newark; and Centro de Biologi\u0301a Molecular \u201cSevero Ochoa\u201d (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Auto\u0301noma de Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuko","family":"Yatani","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine &amp; Dentistry of New Jersey, New Jersey Medical School, Newark; and Centro de Biologi\u0301a Molecular \u201cSevero Ochoa\u201d (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Auto\u0301noma de Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesu\u0301s","family":"Avila","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine &amp; Dentistry of New Jersey, New Jersey Medical School, Newark; and Centro de Biologi\u0301a Molecular \u201cSevero Ochoa\u201d (J.A.), Facultad de Ciencias, Campus de Cantoblanco, Universidad Auto\u0301noma de Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Sadoshima","sequence":"additional","affiliation":[{"name":"From the Cardiovascular Research Institute (S.H., P.Z., H.T., J.G., J.P.M., S.G., C.H., A.Y., J.S.), Department of Cell Biology and Molecular Medicine, University of Medicine &amp; 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