Poly(ADP-ribose) polymerase inhibition prevents homocysteine-induced endothelial dysfunction in the isolated rat...

Recent studies have clearly shown that there is a relationship between hyperhomocysteinemia and endothelial dysfunction. However, the effect of poly(ADP-ribose) polymerase (PARP) inhibition on homocysteine (Hcy)-induced endothelial damage has not been investigated. In this study, we investigated whether the loss of endothelial function in rat aortic rings preincubated with Hcy is dependent upon the PARP pathway within the vasculature. Preincubation of rat aortic rings with Hcy (1 mmol/l; 180 min) significantly inhibited endothelium-dependent relaxation in this tissue. This inhibitory effect was significantly reduced in the presence of both superoxide dismutase (100 U ml(-1)) and catalase (100 U ml(-1)) together with Hcy. Similarly, preincubation for 180 min with either N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride (PJ34; 3 micromol/l) or 3-aminobenzamide (3 mmol/l), structurally different PARP inhibitors, also significantly prevented the development of endothelial dysfunction induced by Hcy. Further incubation of aortic rings with these PARP inhibitors for 60 min after exposure to Hcy for 180 min, at least in part, improved the endothelium-dependent relaxation responses. Thus, our results suggest that intraendothelial PARP activation may be associated with endothelial dysfunction in hyperhomocysteinemic conditions and that inhibition of this pathway may present a novel pharmacological approach to prevent Hcy-induced endothelial damage. Suprisingly, inhibition of the PARP pathway not only prevents the endothelial dysfunction mediated by Hcy, but is also able to rapidly improve it.