See related article, pages 711–719 Unlike the explosive hyperplastic growth that occurs during early embryonic development, neonatal and adult cardiomyocytes undergo hypertrophy as a consequence of a much more subtle increase in the fractional growth rate of the heart. Both physiological and pathological hypertrophy results from mechanical and neurohormonal signals (and their downstream effectors) that tend to increase the rate of cardiac protein synthesis. These growth-promoting pathways are counterbalanced by signaling molecules that tend to inhibit or attenuate the prohypertrophic growth response.1 In this issue of Circulation Research , Jeong et al2 continue to add to a growing list of negative regulators of cardiomyocyte hypertrophy, and describe how PICOT (protein kinase C–interacting cousin of thioredoxin) may function to inhibit the calcineurin (CnA)–nuclear factor of activated T cells (NFAT) signaling pathway responsible for regulating specific aspects of the hypertrophic phenotype. PICOT was first identified in 2000 by Witte et al in a yeast 2-hybrid screen of protein kinase C (PKC)θ-interacting proteins.3 These authors used full-length, catalytically inactive PKCθ to screen a Jurkat T-cell lymphoma cDNA library. They identified a highly conserved, 37.5-kDa cytoplasmic protein containing at least 2 functional domains. The N-terminal, PKCθ binding domain shared sequence homology with the thioredoxin family of proteins but lacked the conserved Cys-Gly-Pro-Cys motif essential for enzyme activity. The C-terminal domain contained 2 tandem repeats, now called PICOT homology (PIH) domains that are shared by proteins expressed in a …