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02 May 2003

Poly(ADP-ribose) polymerase (PARP) activation is an early event in angiotensin-induced cardiovascular disorders

C. Szabo, P. Pacher, K. Komjati, J. Mabley, R. Benko, M. Kollai, M. Kollai

Med Sci Monit 2003; 9(1): 68- :: ID: 15209


Angiotensin II (ANG II) is a well-established participant in many cardiovascular disorders. Recent work demonstrated that infusion of ANG II at sub-pressor doses induces the formation of 3-nitrotyrosine (a stable biomarker of tissue peroxynitrite formation). Here we investigated the role of PARP, a multifunctional nuclear enzyme in the development of AII-induced endothelial dysfunction in the rat. AII infusion to Sprague-Dawley rats (200 ng/kg/min) for 7 days induced the development of endothelial dysfunction, as assessed by the endothelium-dependent relaxant responses to acetylcholine in the thoracic aorta ex vivo. This endothelial dysfunction was sustained when AII was infused at the same rate for an additional 1 week period.The PARP inhibitors PJ34 [2] or INO-1001 (J Am Coll Surg, in press, 2002) at doses of 20 mg/kg/day, starting from Day 1, prevented the development of the endothelial dysfunction. Administration of PJ34 or INO-1001 for the second week only, restored normal endothelial function. Immunohistochemical detection of poly(ADP-ribose) confirmed that the PARP inhibitors blocks vascular PARP activation in the AII-treated animals. PARP activation may play an early role in the pathogenesis of various AII-mediated vascular diseases.References: 1.Virág L, Szabó C: The therapeutic potential of PARP inhibition. Pharmacological Reviews, 2002; 54: 375-429 2.Soriano FG, Virág L, Jagtap P et al: Diabetic endothelial dysfunction: the role of poly (ADP-ribose) polymerase activation. Nature Medicine, 2001; 7: 108-113 3.Pacher P, Mabley JG, Soriano FG et al: Activation of poly(ADP-ribose) polymerase contributes to the endothelial dysfunction associated with hypertension and aging. Int J Mol Med, 2002; 9: 659-664

Keywords: vascular dysfunction, endothelium-dependent relaxation, angiotensin, Nitric Oxide



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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750