Effects of inhibition of poly(adenosine diphosphate-ribose) synthase on acute cardiac allograft rejection

Transplantation
Yulin LiuP J Cannon

Abstract

Nitric oxide synthase (NOS)-2 is expressed during acute cardiac allograft rejection in association with death of heart muscle cells. The nuclear enzyme poly(adenosine diphosphate [ADP]-ribose) synthase (PARS) is activated by agonists such as NO and peroxynitrite, which cause single-strand DNA breaks; PARS, in turn can promote both necrosis and apoptosis. To investigate the hypothesis that NO produced by NOS-2 in cardiomyocytes activates PARS and contributes to heart muscle cell death by apoptosis, experiments were performed using a heterotopic rat abdominal heart transplant model and cytokine-stimulated heart muscle cells in tissue culture. Cardiac allografts were treated after transplantation with either the PARS inhibitor 5-aminoisoquinolinone at 3 mg/kg subcutaneously daily or with vehicle. Isolated purified adult rat cardiomyocytes incubated with cytokines to induce NOS-2 were treated in vitro with another PARS inhibitor, 3-aminobenzamide (3AB). PARS inhibition increased cardiac-allograft survival from 6 +/- 2 to 10 +/- 3 days (n=6, n=6, P<0.05). The inflammatory infiltrate, NOS-2-positive macrophages, myocyte apoptosis, and myocyte content of nitrotyrosine and poly(ADP-ribose) were significantly decreased in PARS inhibited...Continue Reading

References

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Citations

Feb 2, 2013·Molecular Aspects of Medicine·Nicola J Curtin, Csaba Szabo
Oct 28, 2008·Biochemical and Biophysical Research Communications·Dirk M MaybauerDaniel L Traber
Jul 19, 2008·Free Radical Biology & Medicine·Jeannette Vásquez-VivarGalen M Pieper
Jun 15, 2006·Transplant International : Official Journal of the European Society for Organ Transplantation·Gábor SzabóSiegfried Hagl
Jul 5, 2006·The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation·Gábor SzabóThomas J Dengler
Feb 23, 2008·Free Radical Biology & Medicine·Galen M Pieper, Allan M Roza

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