Beschreibung:
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<jats:underline>Purpose:</jats:underline>
Acute coronary syndromes (ACS) have been associated with sCD40 Ligand (sCD40L) release. Endothial cells are located at the interface between the blood and parenchymal cells and take active part in many physiological and pathologic processes, including inflammation. It has been suggested that CD40L is a key player in the pathogenesis of atherosclerosis and ACS, originating from endothelial cells. When sCD40L is present in human plasma during ACS, it is mainly derived from activated platelets. This may lead to activation of endothelial cells resulting in atherosclerosis and eventually atherothrombosis. Therefore, the aim of the present study was to investigate differential gene expression profiles of endothelial cells after stimulation with sCD40L.
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<jats:underline>Methods:</jats:underline>
Human endothelial cells (HUVEC) were stimulated with sCD40L for 2 hours. Differential gene expression patterns were evaluated with Oligonucleotide microarray hybridization (UG-U133A, Affymetrix Inc, Santa Clara, CA). Significantly up-regulated gene expression was confirmed and quantitated by Real-time-PCR as well as ELISA. In serum from ACS patients expression of sCD40L was correlated with these up-regulated genes products.
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<jats:underline>Results:</jats:underline>
Stimulation of HUVEC with sCD40L leads to a profound release of proinflammatory mediators like IL-8, ICAM1, ISGF3 as well as MCP-1 on a transcriptional level. In addition, gene expression profiling revealed a highly significant increase in expression of the macrophage inflammatory protein 2 (MIP-2), also known as GRO-beta or CXCL2. This was quantitated as approximately 30 fold up-regulation by real-time-PCR as well as in ELISA analysis (8 fold at 8 to 24 hours) derived from supernations. In clinical serum samples from ACS patients there was a highly significant correlation between sCD40L and MIP-2 levels (r = 0.88, p < 0.01)
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<jats:underline>Conclusion:</jats:underline>
Proinflammatory mediators as well as MIP-2 play an important role in the chemoattraction of macrophages, which underlines the key role of CD40L as a link between thrombotic events, e.g ACS, and inflammatory processes, e.g. atherosclerosis. Therefore targeting MIP-2 up-regulation might be a potential approach to prevent the progression of atherosclerotic diseases as well as a new therapeutic approach to treat ACS.
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