PATHOPHYSIOLOGY OF THE ENDOTHELIUM - THE EFFECT OF THE CYCLOSPORINE-AAND FK-506 ON INTRACELLULAR SIGNALING PATHWAYS AND GENE-EXPRESSION INENDOTHELIUM

The primary action of CsA and FK506 is lo block rile expression of lym phokines produced by T-cells. Damage to the vascular endothelium is on e oi their most well known side effects. Little is known about the mol ecular changes in signal transduction and gene expression induced by C sA on the endothelium. A CsA-dependent up-regulation of eNOS mRNA was detected in bovine aortic endothelial cells. A similar result was obse rved with FK506. CsA appears to increase eNOS mRNA mainly by increasin g the rate of transcription. Since CsA and FK506 induce an increase in reactive oxygen species in the bovine endothelium, a role of peroxyni trite in the vascular damage by immunosuppressants should be ruled out . An implication of calcineurin and NF-AT in this toxic effect remains to be shown. A molecular description of the immunosuppressants associ ated toxic mechanisms should be helpful in the design of new immunosup pressive molecules.