Gene Expression Profiling of Inflamed Human Endothelial Cells and Influence of Activated Protein C
Copyright policy )Gene Expression Profiling of Inflamed Human Endothelial Cells and Influence of Activated Protein C
Background— During systemic inflammation, activation of vascular endothelium by proinflammatory cytokines leads to hypotension, microvascular thrombosis, and organ damage. Recent data suggest a link between coagulation and inflammation through the activated protein C (APC) pathway. We studied gene expression profiles in human coronary artery endothelial cells (HCAECs) exposed to proinflammatory stimuli and the influence of APC on expression of candidate genes regulated by these stimuli. Methods and Results— HCAECs were stimulated with interleukin-1β, interferon-γ, and tumor necrosis factor-α. In gene expression profiling, 400 of 8400 genes were regulated >2-fold. Verification of selected candidate genes was achieved by measuring expression of mRNA species by real-time polymerase chain reaction, cytokine secretion by ELISA, and metabolites of tetrahydrobiopterin (BH4) biosynthesis by high-performance liquid chromatography. BH4 synthesis, interleukin-6, interleukin-8, monocyte chemotactic protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were downregulated by APC at the transcriptional and protein level. Endothelial nitric oxide synthase, endothelial adhesion molecule, and vascular cell adhesion molecule-1 were not affected by APC. Activities of transcription factors c-Fos, FosB, and c-Rel were inhibited by APC in inflamed HCAECs. Conclusions— Our study revealed a novel antiinflammatory mechanism of APC-dependent gene regulation in HCAECs since c-Fos–dependent induction of MCP-1 and ICAM-1 was suppressed. APC downregulates expression and activity of genes related to inflammation, most pronounced under intermediate or mild inflammatory conditions.
- University Hospital of Zurich Switzerland
- University of Zurich Switzerland
- University Children's Hospital Zurich Switzerland
Nitric Oxide Synthase Type III, Gene Expression Profiling, NF-kappa B, Receptors, Cell Surface, Coronary Vessels, Blood Coagulation Factors, Biopterins, Interferon-gamma, Gene Expression Regulation, Cytokines, Humans, Receptor, PAR-2, Receptor, PAR-1, Receptors, Thrombin, RNA, Messenger, Nitric Oxide Synthase, Cell Adhesion Molecules, Cells, Cultured, Interleukin-1, Protein C
Nitric Oxide Synthase Type III, Gene Expression Profiling, NF-kappa B, Receptors, Cell Surface, Coronary Vessels, Blood Coagulation Factors, Biopterins, Interferon-gamma, Gene Expression Regulation, Cytokines, Humans, Receptor, PAR-2, Receptor, PAR-1, Receptors, Thrombin, RNA, Messenger, Nitric Oxide Synthase, Cell Adhesion Molecules, Cells, Cultured, Interleukin-1, Protein C
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).96 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!