Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a new promising target for prevention and treatment of cardiac hypertrophy and heart failure. There are three delta isoforms of CaMKII in the heart and previous studies focused primarily on delta B and delta C types. Here we report the delta A isoform of CaMKII is also critically involved in cardiac hypertrophy. We found that delta A was significantly upregulated in pathological cardiac hypertrophy in both neonatal and adult models. Upregulation of delta A was accompanied by cell enlargement, sarcomere reorganization and reactivation of various hypertrophic cardiac genes including atrial natriuretic factor (ANF) and beta-myocin heavy chain (beta-MHC). Studies further indicated the pathological changes were largely blunted by silencing the delta A gene and an underlying mechanism indicated selective interference with the HDAC4-MEF2 signaling pathway. These results provide new evidence for selective interfering cardiac hypertrophy and heart failure when CaMKII is considered as a therapeutic target. (C) 2011 Elsevier Inc. All rights reserved.