It is well known that granulocytes increase infarct size after reperfusion of the ischemic myocardium, and that monocytes promote atherogenesis. Those cells are also believed to play a contributory role in pathogenesis of coronary restenosis as response to arterial injury during balloon angioplasty. The adhesion of those leukocytes to the vascular endothelium is a prerequisite for their recruitment and accumulation in the lesion. Inflammatory mediators likely to occur under those conditions, e.g., histamine, thrombin, oxygen-derived free radicals (ODFR), interleukin (IL)-1, tumor necrosis factor (TNF)-α, and activated complement factors, induce in a distinct time course the (transient) expression of the leukocyte adhesion molecules P-selectin, E-selectin, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 on the endothelium. Only VCAM-1 is specific for monocytes; the others mediate the binding and subsequent extravasation of both monocytes and granulocytes. The response to the relevant inflammatory mediators, except for extracellularly produced ODFR, is coupled via specific receptors on the surface of the endothelium to specific signal transduction pathways and, except for P-selectin (early response), is directly dependent on protein synthesis (intermediate and late response). Protein kinase-C-induced phosphorylation of transcription factors is often shown to be involved. Protein synthesis is preceded by increased transcription of mRNA that is regulated in part by the transcription factor NF-κB. Indications have been obtained that intracellularly produced ODFR may be involved in the translocation of this transcription factor. This rapidly increasing insight into the mechanisms by which granulocytes and monocytes adhere to the vascular endothelium will open new avenues to therapeutic strategies to alleviate tissue damage in cardiovascular diseases.
Address correspondence and reprint requests to Dr. J. M. J. Lamers at the Department of Biochemistry, Cardiovascular Research Institute (COEUR), Erasmus University Rotterdam (EUR), P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
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