15 research outputs found
Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells.
Endothelial cells (ECs) are critical determinants of vascular homeostasis and inflammation, but transcriptional mechanisms specifying their identities and functional states remain poorly understood. Here, we report a genome-wide assessment of regulatory landscapes of primary human aortic endothelial cells (HAECs) under basal and activated conditions, enabling inference of transcription factor networks that direct homeostatic and pro-inflammatory programs. We demonstrate that 43% of detected enhancers are EC-specific and contain SNPs associated to cardiovascular disease and hypertension. We provide evidence that AP1, ETS, and GATA transcription factors play key roles in HAEC transcription by co-binding enhancers associated with EC-specific genes. We further demonstrate that exposure of HAECs to oxidized phospholipids or pro-inflammatory cytokines results in signal-specific alterations in enhancer landscapes and associate with coordinated binding of CEBPD, IRF1, and NFκB. Collectively, these findings identify cis-regulatory elements and corresponding trans-acting factors that contribute to EC identity and their specific responses to pro-inflammatory stimuli
Recommended from our members
Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells.
Endothelial cells (ECs) are critical determinants of vascular homeostasis and inflammation, but transcriptional mechanisms specifying their identities and functional states remain poorly understood. Here, we report a genome-wide assessment of regulatory landscapes of primary human aortic endothelial cells (HAECs) under basal and activated conditions, enabling inference of transcription factor networks that direct homeostatic and pro-inflammatory programs. We demonstrate that 43% of detected enhancers are EC-specific and contain SNPs associated to cardiovascular disease and hypertension. We provide evidence that AP1, ETS, and GATA transcription factors play key roles in HAEC transcription by co-binding enhancers associated with EC-specific genes. We further demonstrate that exposure of HAECs to oxidized phospholipids or pro-inflammatory cytokines results in signal-specific alterations in enhancer landscapes and associate with coordinated binding of CEBPD, IRF1, and NFκB. Collectively, these findings identify cis-regulatory elements and corresponding trans-acting factors that contribute to EC identity and their specific responses to pro-inflammatory stimuli
Metalloproteinase Processing of HBEGF Is a Proximal Event in the Response of Human Aortic Endothelial Cells to Oxidized Phospholipids
An Epoxyisoprostane Is a Major Regulator of Endothelial Cell Function
The goal of these studies was to
determine the effect of 5,6-epoxyisoprostane,
EI, on human aortic endothelial cells (HAEC). EI can form as a phospholipase
product of 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-<i>sn</i>-glycero-3-phosphocholine, PEIPC, a proinflammatory molecule that
accumulates in sites of inflammation where phospholipases are also
increased. To determine the effect of EI on HAEC, we synthesized several
stereoisomers of EI using a convergent approach from the individual
optically pure building blocks, the epoxyaldehydes <b>5</b> and <b>6</b> and the bromoenones <b>14</b> and <b>16</b>.
The desired stereoisomer of EI can be prepared from these materials
in only six operations, and thus, large amounts of the product can
be obtained. The trans/trans isomers had the most potent activity,
suggesting specificity in the interaction of EI with the cell surface.
EI has potent anti-inflammatory effects in HAEC. EI strongly inhibits
the production of MCP-1, a major monocyte chemotactic factor, and
either decreases or minimally increases the levels of 10 proinflammatory
molecules increased by PEIPC. EI also strongly down-regulates the
inflammatory effects of IL-1β, a major inflammatory cytokine.
Thus EI, a hydrolytic product of PEIPC, has potent anti-inflammatory
function