Functional and structural investigation of the role of poly (adp-ribose) polymerase (parp) pathway on endothelin-1 (et-1)-induced endothelial dysfunction in rat thoracic aorta

daha sonra ekleneceThe aim of this study was to investigate whether activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) contributes to the development of endothelin-1 (ET-1)-induced endothelial dysfunction. In order to evaluate vascular reactivity,isometric tension studies were performed in response to vasodilator agents, acetylcholine(ACh) and sodium nitroprusside (SNP), and constrictor agents, potassium chloride (KCl) and phenylephrine (Phe). The results of this study demonstrated that incubation of thoracic artery rings with ET-1 (10-3 M, 18 h) resulted in significant inhibition of response to ACh (an endothelium-dependent vasodilator) while SNP (an endotheliumindependent vasodilator)-induced relaxation was not changed significantly. Moreover, the contractile response to Phe significantly increased in arteries that were incubated with ET-1, compared with controls. To investigate mechanisms of ET-1 action, additional sets of experiments involving rings incubation with ET-1 alone or with addition of polyethylene glycol?superoxide dismutase (PEG-SOD, a cell permeabl superoxide radical scavenger, 41 U/ml) plus apocynin (a NADPH oxidase inhibitor, 300 µM), and PJ34 (an inhibitor of polyADP-ribose polymerase, 3x10-6 M) for 18 hours, and both relaxant and constrictor responses were evaluated again. The findings of our study clearly show that all these co-treatments significantly prevented the development of endothelial dysfunction induced by ET-1. Furthermore, the effect of ET-1 on Pheinduced contraction was significantly inhibited by the concomitant incubation with either PEG-SOD plus apocynin, or PJ34. The results of this study suggest that ET-1causes a significant alteration in vascular reactivity of thoracic artery, and this alteration seems to be via oxidative stress in thoracic artery endothelium with subsequent DNA damage and activation of PARP pathway.Key words: Endothelial dysfunction, endothelin-1 (ET-1), poly(ADP-ribose) polymerase (PARP)ktir