Dataset Information

CYP2J2 Modulates Diverse Transcriptional Programs in Adult Human Cardiomyocytes.

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.

SUBMITTER: Evangelista EA

PROVIDER: S-EPMC7093536 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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CYP2J2 Modulates Diverse Transcriptional Programs in Adult Human Cardiomyocytes.

Evangelista Eric A EA Aliwarga Theresa T Sotoodehnia Nona N Jensen Paul N PN McKnight Barbara B Lemaitre Rozenn N RN Totah Rheem A RA Gharib Sina A SA

Scientific reports 20200324 1

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 CY ...[more]

PMID: 32210298

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Project description:BackgroundSarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that most commonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated in bronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease.MethodsWe recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjects underwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized to an Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expression between subjects with sarcoidosis vs.ControlsTo better elucidate pathways differentially activated between these groups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles.ResultsSarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only two were on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expression between sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previously described immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using an integrative computational approach we constructed a modular network of over 80 gene sets that were highly enriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-related processes including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling. Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity, highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis.ConclusionsBAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involved in immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar resident immune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation may modulate disease progression.

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CYP2J2 Modulates Diverse Transcriptional Programs in Adult Human Cardiomyocytes.

Publications

CYP2J2 Modulates Diverse Transcriptional Programs in Adult Human Cardiomyocytes.

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