Abstract
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 arachidonic acid to epoxyeicosatrienoic acids, which, in turn, have been implicated in mediating several cardiovascular conditions. Using a proteomic approach, we found that CYP2J2 expression is lower in cardiac tissue from patients with cardiomyopathy compared to controls. In order to better elucidate the complex role played by CYP2J2 in cardiac cells, we performed targeted silencing of CYP2J2 expression in human adult ventricular cardiomyocytes 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 in cardiovascular health and disease.
Highlights
Cytochrome P450s (CYPs) are a superfamily of enzymes involved in a wide range of physiological processes
Our results demonstrate that in the presence of a known CYP2J2 inhibitor, danazol (DAN), there is a significant drop in terfenadine hydroxylation in cells treated with siRNA, indicating that the observed changes in metabolism during siRNA treatment is due to reduction in CYP2J2 protein level and activity
We first investigated CYP2J2 protein levels using proteomic mass spectrometry in ventricular tissue obtained from a cohort of individuals without heart disease and patients with cardiomyopathy
Summary
Cytochrome P450s (CYPs) are a superfamily of enzymes involved in a wide range of physiological processes These heme-containing monooxygenases have been extensively studied with the aim of understanding their role in the biotransformation and clearance of drugs and toxins[1,2,3]. Members of CYP2 family oxidize several polyunsaturated fatty acids (PUFAs), many of which have roles in various cell response and signal transduction pathways[4]. Delineating how these enzymes affect and interact with other molecules in cellular response cascades could be critical in understanding the mechanisms by which cells respond to environmental changes and external stressors and may identify new therapeutic targets. We used siRNA to effectively silence CYP2J2 expression and performed RNA-sequencing (RNA-seq) and bioinformatics analyses to identify CYP2J2-regulated transcriptional programs in human cardiomyocytes and putative targets for future mechanistic and therapeutic studies
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