Myocardial infarction (MI) is often followed by heart failure (HF), but the mechanisms precipitating the transition to HF remain largely unknown. A genomic profile was performed in a monkey model of MI, from the myocardium adjacent to chronic (2-month) MI followed by 3 weeks of pacing to develop HF. The transcript of the gene encoding the cell cycle-related kinase (CCRK) was down-regulated by 50% in HF heart compared with control (p < 0.05), which was confirmed by quantitative PCR. The CCRK sequence cloned from a heart library showed a conservation of the N-terminal kinase domain when compared with the "generic" isoform cloned previously but a different C-terminal half due to alternative splicing with frameshift. The homology of the cardiac sequence was 100% between mice and humans. Expression of the corresponding protein, measured upon generation of a monoclonal antibody, was limited to heart, liver, and kidney. Upon overexpression in cardiac myocytes, both isoforms promote cell growth and reduce apoptosis by chelerythrine (p < 0.05 versus control). Using a yeast two-hybrid screening, we found an interaction of the generic but not the cardiac CCRK with cyclin H and casein kinase 2. In addition, only the generic CCRK phosphorylates the cyclin-dependent kinase 2, which was accompanied by a doubling of myocytes in the S and G 2 phases of the cell cycle (p < 0.05 versus control). Therefore, the heart expresses a splice variant of CCRK, which promotes cardiac cell growth and survival; differs from the generic isoform in terms of protein-protein interactions, substrate specificity and regulation of the cell cycle; and is downregulated significantly in HF.Because the fully differentiated cardiac myocyte has a limited capacity for regeneration, most forms of heart disease, including ischemic heart disease and heart failure (HF), 2 are characterized by a loss of cardiomyocytes (1-3). Therefore, deciphering the molecular mechanisms balancing cell growth and apoptosis may help develop strategies to improve the prognosis of both ischemic heart disease and HF, particularly with regard to stem cell therapy (4). Our previous studies have shown that genomic profiling in large mammalian models of heart disease allows the detection of novel potential candidates to promote cardiac cell growth and survival in a context of reversible ischemia or pressure overload (5, 6). In the present study, we extended this investigation to a model of postischemic cardiomyopathy in monkeys. We reasoned that a nonhuman primate model would be ideal, since it is phylogenetically and genetically closer to humans. Genomic profile by DNA microarrays in that model revealed the down-regulation of the cell cycle-related kinase (CCRK) after development of HF. Although this protein has not been characterized in the heart before, it is known that CCRK plays a major role in promoting the growth of cancer cells (7). Therefore, the goal of the present study is to characterize the expression of CCRK in the normal and failing heart and to determine whether this k...