REGULATION OF ENDOTHELIAL NO SYNTHASE EXPRESSION BY CYCLOSPORINE-A INBOVINE AORTIC ENDOTHELIAL-CELLS

The introduction of cyclosporin A (CsA) is considered a cornerstone ad vance in immunosuppresion. However, serious side effects such as hyper tension have fostered an important body of research regarding their pa thophysiology. Although the participation of several vasoactive factor s in the hypertensive response has been described, recent attention ha s focused on endothelium-derived vasoactive factors, and several repor ts describe an overproduction of endothelin-1 and a deficient endothel ium-dependent vasodilation. In the case of the latter, no definitive c lues for the precise molecular mechanisms have been provided. We demon strate that endothelial cells in culture synthesize more NO in the pre sence of CsA for 24 h in a concentration-response manner. This augment ation is correlated with a threefold increase in the endothelial const itutive NO synthase (ecNOS) transcript, which is time dependent and ma ximal at 24 h. The CsA-induced increase in ecNOS mRNA expression was b locked by actinomycin D but unaltered by cycloheximide. Levels of ecNO S protein were also enhanced by CsA after 24 h. These data establish t hat NO synthesis is moderately enhanced in endothelial cells exposed t o CsA for long periods of time and describe a new mode of regulating e cNOS gene expression.