Published Online
on October 25, 2004

A more recent version of this article appeared on November 2, 2004

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Submitted on October 3, 2003
Revised on May 17, 2004
Accepted on May 26, 2004

Gene Expression Profiling of Inflamed Human Endothelial Cells and Influence of Activated Protein C

Nicola Franscini MD, Esther B. Bachli MD, Nenad Blau PhD, Maria-Sybille Leikauf BS, Andreas Schaffner MD, and Gabriele Schoedon PhD^*

From the Medical Clinic B Research Unit (N.F., A.S., G.S.) and Medical Clinic A (E.B.B., M.L.), Department of Medicine, University Hospital of Zürich; and Department of Pediatrics, Division of Clinical Chemistry and Biochemistry, University Childrens’ Hospital, University of Zürich (N.B.), Zürich, Switzerland.

^* To whom correspondence should be addressed. E-mail: klinsog{at}usz.unizh.ch.

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-1, interferon-, and tumor necrosis factor-. 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.

Key words: endothelium • genes • inflammation • interleukins • cell adhesion molecules

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