See related article, pages 748–755 Pressure overload stimulation of the heart stimulates a medley of signaling leading to hypertrophic remodeling. This compensatory effort to increase cardiac output depends on harmonious blending of kinase activities. Participation of protein kinase C (PKC) isoforms in hypertrophic signaling following agonist stimulation or pressure overload is unequivocal, but teasing out the specific roles for various isoform subtypes has been a frustrating endeavor. Researchers have approached this issue by tinkering with PKC isoform kinase activities via overexpression, activating/interfering peptides, or creation of knockout mice.1 Information gleaned from these studies has made 1 point abundantly clear: PKC isoforms have a propensity for shared activation stimuli and common substrate specificities. As such, altering the activity of 1 PKC isoform almost invariably has consequences for the expression/activation/localization of other family members that normally lead to coordinated PKC responses when the heart is subjected to stress. In the case of a study by Klein et al2 in this issue, losing PKCe prompts changes in PKCδ that spell bad news for cardiac structure and function. Klein et al identify cross-regulation between the novel PKCδ and PKCe isoforms in the heart. They demonstrate that PKCδ protein expression is similar in normal and knockout PKCe−/− mice under basal conditions and in normal hearts subjected to pressure overload, but that PKCδ protein expression and phosphorylation levels are increased in PKCe−/− hearts following pressure overload. Prior studies by other groups show that pressure overload-induced hypertrophy leaves PKCe unaffected, whereas PKCδ phosphorylation as well as protein expression level are significantly increased.3,4 Isoform-specific activation studies using selective peptides that show induction of either PKCe or PKCδ promote similar prohypertrophic effects.5 Klein et al found hypertrophic stimulation in the absence of PKCe provokes a compensatory rise in PKCδ activity, reinforcing the …