http://repub.eur.nl/res/aut/12497/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/20406/ 1999-04-28T00:00:00Z The accumulation of circulating monocytes in the vessel wall is an important aspect of the pathogenesis of atherosclerosis and allied problems such as restenosis after percutaneous transluminal angioplasty (PTA). Three distinct steps can be distinguished in the stimulated accumulation of these cells. First there is an increased rolling, followed by firm adhesion, and finally migration of the monocytes in the direction of a chemotactic gradient. These different steps are regulated by specific endothelial cell adhesion molecules. In general rolling is mediated by the selectins, while immunoglobulin supergene family member vascular cell adhesion molecule (VCAM)-l specifically mediates rolling and fiml adhesion of monocytes. VCAM-I may thus enhance the local accumulation of monocytes even in the absence of seledin expression. In experimental models of atherosclerosis VCAM-I expression is an early feature of the atheromatous lesion, which suggests that VCAM-l plays a role in the initiation and progression of the atherosclerotic plaque. The expression of VCAM-l on endothelial cells is induced by the cytokine tumor necrosis factor a (TNF) and presumably regulated at the transcriptional level in part through the activation of the transcription factor nuclear factor (NF) KB. TNF stimulates intracellular signalling in endothelial cells through the production of lipid second messengers and mitogen activated protein kinase cascades. It has been hypothesized that reactive oxygen species (ROS), such as hydrogen peroxide, function as intracellular second messengers in the signal transduction of TNF. This putative role for ROS may comprise a novel mechanism of intracellular signalling next to protein phosphorylation. the cyclic nucleotide system, and signalling through the inositol phosphates and intracellular calcium. In the present thesis we have investigated the possible role of ROS as second messengers in the TNF stimulated expression of VCAM-l by endothelial cells. http://repub.eur.nl/res/pub/5086/ 1995-01-01T00:00:00Z Background The purpose of this pilot study was to identify biological risk factors for restenosis after percutaneous transluminal coronary angioplasty (PTCA) to predict the long-term outcome of PTCA before treatment. Methods and Results To investigate whether blood granulocytes and monocytes could determine luminal renarrowing after PTCA, several characteristics of these phagocytes were assessed before angioplasty in 32 patients who underwent PTCA of one coronary artery and who had repeat angiograms at 6-month follow-up. The plasma levels of interleukin (IL)-1ß, tumor necrosis factor-, IL-6, fibrinogen, C-reactive protein, and lipoprotein(a) before angioplasty were assessed as well. We found that the expression of the membrane antigens CD64, CD66, and CD67 by granulocytes was inversely associated with the luminal renarrowing normalized for vessel size (relative loss) at 6 months after PTCA, while the production of IL-1ß by stimulated monocytes was positively associated with the relative loss. Next, these univariate predictors were corrected for the established clinical risk factors of dilation of the left anterior descending coronary artery and current smoking, which were statistically significant classic predictors in our patient group. Only the expression of CD67 did not predict late lumen loss independent of these established clinical risk factors. Multiple linear regression analysis showed that luminal renarrowing could be predicted reliably (R2=.65; P<.0001) in this patient group on the basis of the vessel dilated and only two biological risk factors that reflect the activation status of blood phagocytes, ie, the expression of CD66 by granulocytes and the production of IL-1ß by stimulated monocytes. Conclusions The results of the present study indicate that activated blood granulocytes prevent luminal renarrowing after PTCA, while activated blood monocytes promote late lumen loss. To validate this new finding, further study in an independent patient group is required.