Alloantigen recognition in the mouse heterotopic model of OB

Abstract

(CyA) has been linked to the development of accelerated cardiac allograft vasculopathy (CAV). CyA may promote CAV by (i) impairing nitric oxide (NO) mediated vasodilatation, (ii) stimulating oxidant production and (iii) downregulating Fas-Ligand (FasL) expression thereby leading to neutrophil migration. In the present study, we hypothesized that the NO synthase cofactor, tetrahydrobiopterin (BH4), would attenuate the deleterious effects of CyA via the aforementioned pathways. Methods: The effects of BH4 (0.1mM) on endothelium dependent and independent relaxation were assessed in rat aortae with and without exposure to CyA (25mg/kg/day for 7 days). Lucigenin chemiluminiscence was employed to examine the effects of CyA BH4 on coronary artery superoxide production. FasL expression was measured in cultured human coronary endothelial cells exposed to CyA BH4. Results: CyA treated aortae displayed impaired endothelium dependent vasodilation (%Emax 67 7 vs 91 9, p 0.05), with no change in endothelium independent vasodilation. BH4 attenuated the CyA-induced endothelial dysfunction (%Emax 76 5, p 0.05). BH4 also attenuated the CyA-induced increase in superoxide production (BH4 1250 56 cpm/mg vs. CYA: 1845 81 vs control 848 86, p 0.05). Coronary endothelial FasL expression was not affected by either CyA or BH4. Conclusions: BH4 attenuates CyA induced endothelial dysfunction and superoxide production. BH4 may be an important cellular target for the prevention of cardiac allograft vasculopathy related to cyclosporin induced endothelial injury.