{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T14:11:59Z","timestamp":1791987119172,"version":"4.4.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"7","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,2,17]]},"abstract":"<jats:p>Acute and chronic injuries to the heart result in perturbation of intracellular calcium signaling, which leads to pathological cardiac hypertrophy and remodeling. Calcium\/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the transduction of calcium signals in the heart, but the specific isoforms of CaMKII that mediate pathological cardiac signaling have not been fully defined. To investigate the potential involvement in heart disease of CaMKII\u03b4, the major CaMKII isoform expressed in the heart, we generated CaMKII\u03b4-null mice. These mice are viable and display no overt abnormalities in cardiac structure or function in the absence of stress. However, pathological cardiac hypertrophy and remodeling are attenuated in response to pressure overload in these animals. Cardiac extracts from CaMKII\u03b4-null mice showed diminished kinase activity toward histone deacetylase 4 (HDAC4), a substrate of stress-responsive protein kinases and suppressor of stress-dependent cardiac remodeling. In contrast, phosphorylation of the closely related HDAC5 was unaffected in hearts of CaMKII\u03b4-null mice, underscoring the specificity of the CaMKII\u03b4 signaling pathway for HDAC4 phosphorylation. We conclude that CaMKII\u03b4 functions as an important transducer of stress stimuli involved in pathological cardiac remodeling in vivo, which is mediated, at least in part, by the phosphorylation of HDAC4. These findings point to CaMKII\u03b4 as a potential therapeutic target for the maintenance of cardiac function in the setting of pressure overload.<\/jats:p>","DOI":"10.1073\/pnas.0813013106","type":"journal-article","created":{"date-parts":[[2009,1,28]],"date-time":"2009-01-28T22:08:45Z","timestamp":1233180525000},"page":"2342-2347","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":409,"title":["The \u03b4 isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload"],"prefix":"10.1073","volume":"106","author":[{"given":"Johannes","family":"Backs","sequence":"first","affiliation":[{"name":"Department of Internal Medicine III University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany;"},{"name":"Departments of bMolecular 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