CYP2J2 Modulates Diverse Transcriptional Programs in Adult Human Cardiomyocytes

CYP2J2, a member of the Cytochrome P450 family of enzymes, is the most abundant epoxygenase in the heart and has multifunctional properties including bioactivation of epoxyeicosatrienoic acids, which, in turn, have been implicated in mediating several cardiovascular conditions. In order to elucidate the complex role played by CYP2J2 in cardiac tissue, we performed targeted silencing of CYP2J2 expression in human adult cardiomyoctes and interrogated whole genome transcriptional responses. We found that knockdown of CYP2J2 elicits widespread alterations in gene expression of ventricular cardiomyocytes and leads to the activation of a diverse repertoire of programs, including those involved in ion channel signaling, development, extracellular matrix, and metabolism. Several members of the differentially up-regulated ion channel module have well-known pathogenetic roles in cardiac dysrhythmias. By leveraging causal network and upstream regulator analysis, we identified several candidate drivers of the observed transcriptional response to CYP2J2 silencing; these master regulators have been implicated in aberrant cardiac remodeling, heart failure, and myocyte injury and repair. Collectively, our study demonstrates that CYP2J2 plays a central and multifaceted role in cardiomyocyte homeostasis, and provides a framework for identifying critical regulators and pathways influenced by this gene. Adult human cardiomyocte mRNA profiles from culutre after treatmente with CYP2J2 siRNA (n = 3) or scramble siRNA (n = 3 were generated by deep sequencing, using Illumina HiSeq.