{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T23:25:05Z","timestamp":1778282705247,"version":"3.51.4"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2009,4,10]]},"abstract":"<jats:p>\n            Mitogen-activated protein kinase kinase (MKK)4 is a critical member of the mitogen-activated protein kinase family. It is able to activate the c-Jun NH\n            <jats:sub>2<\/jats:sub>\n            -terminal protein kinase (JNK) and p38 mitogen-activated protein kinase in response to environmental stresses. JNK and p38 are strongly implicated in pathological cardiac hypertrophy and heart failure; however, the regulatory mechanism whereby the upstream kinase MKK4 activates these signaling cascades in the heart is unknown. To elucidate the biological function of MKK4, we generated mice with a cardiac myocyte-specific deletion of\n            <jats:italic>mkk4<\/jats:italic>\n            (MKK4\n            <jats:sup>cko<\/jats:sup>\n            mice). In response to pressure overload or chronic \u03b2-adrenergic stimulation, upregulated NFAT (nuclear factor of activated T-cell) transcriptional activity associated with exacerbated cardiac hypertrophy and the appearance of apoptotic cardiomyocytes were observed in MKK4\n            <jats:sup>cko<\/jats:sup>\n            mice. However, when subjected to swimming exercise, MKK4\n            <jats:sup>cko<\/jats:sup>\n            mice displayed a similar level of physiological cardiac hypertrophy compared to controls (MKK4\n            <jats:sup>f\/f<\/jats:sup>\n            ). In addition, we also discovered that MKK4 expression was significantly reduced in heart failure patients. In conclusion, this study demonstrates for the first time that MKK4 is a key mediator which prevents the transition from an adaptive response to maladaptive cardiac hypertrophy likely involving the regulation of the NFAT signaling pathway.\n          <\/jats:p>","DOI":"10.1161\/circresaha.108.188292","type":"journal-article","created":{"date-parts":[[2009,3,6]],"date-time":"2009-03-06T05:09:14Z","timestamp":1236316154000},"page":"905-914","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":63,"title":["Cardiac-Specific Deletion of\n            <i>Mkk4<\/i>\n            Reveals Its Role in Pathological Hypertrophic Remodeling but Not in Physiological Cardiac Growth"],"prefix":"10.1161","volume":"104","author":[{"given":"Wei","family":"Liu","sequence":"first","affiliation":[{"name":"From the Faculty of Medical and Human Sciences (W.L., M.Z., S.P., D.O., M.L., L.N., E.J.C.) and Faculty of Life Sciences (J.J., T.E.K., A.H.W., X.W.), University of Manchester, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Zi","sequence":"additional","affiliation":[{"name":"From the Faculty of Medical and Human Sciences (W.L., M.Z., S.P., D.O., M.L., L.N., E.J.C.) and Faculty of Life Sciences (J.J., T.E.K., A.H.W., X.W.), University of Manchester, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiawei","family":"Jin","sequence":"additional","affiliation":[{"name":"From the Faculty of Medical and Human Sciences (W.L., M.Z., S.P., D.O., M.L., L.N., E.J.C.) and Faculty of Life Sciences (J.J., T.E.K., A.H.W., X.W.), University of Manchester, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sukhpal","family":"Prehar","sequence":"additional","affiliation":[{"name":"From the Faculty of Medical and Human Sciences (W.L., M.Z., S.P., D.O., M.L., L.N., E.J.C.) and Faculty of Life Sciences (J.J., T.E.K., A.H.W., X.W.), University of Manchester, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delvac","family":"Oceandy","sequence":"additional","affiliation":[{"name":"From the Faculty of Medical and Human Sciences (W.L., M.Z., S.P., D.O., M.L., L.N., E.J.C.) and Faculty of Life Sciences (J.J., T.E.K., A.H.W., X.W.), University of Manchester, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomomi E.","family":"Kimura","sequence":"additional","affiliation":[{"name":"From the Faculty of Medical and Human Sciences (W.L., M.Z., S.P., D.O., M.L., L.N., E.J.C.) and Faculty of Life Sciences (J.J., T.E.K., A.H.W., X.W.), University of Manchester, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Lei","sequence":"additional","affiliation":[{"name":"From the Faculty of Medical and Human Sciences (W.L., M.Z., S.P., D.O., M.L., L.N., E.J.C.) and Faculty of Life Sciences (J.J., T.E.K., A.H.W., X.W.), University of Manchester, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludwig","family":"Neyses","sequence":"additional","affiliation":[{"name":"From the Faculty of Medical and Human Sciences (W.L., M.Z., S.P., D.O., M.L., L.N., E.J.C.) and Faculty of Life Sciences (J.J., T.E.K., A.H.W., X.W.), University of Manchester, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur H.","family":"Weston","sequence":"additional","affiliation":[{"name":"From the Faculty of Medical and Human Sciences (W.L., M.Z., S.P., D.O., M.L., L.N., E.J.C.) and Faculty of Life Sciences (J.J., T.E.K., A.H.W., X.W.), University of Manchester, United Kingdom."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth J.","family":"Cartwright","sequence":"additional","affiliation":[{"name":"From the Faculty of Medical and Human Sciences (W.L., M.Z., S.P., D.O., M.L., L.N., E.J.C.) and Faculty of Life Sciences (J.J., T.E.K., A.H.W., X.W.), 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