Genetic Disruption of Poly (ADP-Ribose) Synthetase Inhibits the Expression of P-Selectin and Intercellular Adhesion Molecule-1 in Myocardial Ischemia/Reperfusion Injury

Abstract

The nuclear enzyme poly (ADP-ribose) synthetase (PARS) has been shown to play an important role in the pathogenesis of ischemia/reperfusion injury and circulatory shock. The aim of this study was to investigate whether PARS activity may modulate endothelial-neutrophil interaction. We present evidence that genetic disruption of PARS provides protection against myocardial ischemia and reperfusion injury by inhibiting the expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) and, consequently, by inhibiting the recruitment of neutrophils into the jeopardized tissue. Furthermore, using in vitro studies, we demonstrate that in fibroblasts lacking a functional gene for PARS, cytokine-stimulated expression of ICAM-1 is significantly reduced compared with fibroblasts from animals with a normal genotype. Similarly, in cultured human endothelial cells, oxidative- or cytokine-dependent expression of P-selectin and ICAM-1 is reduced by pharmacological inhibition of PARS by 3-aminobenzamide. These findings provide the first direct evidence that PARS activation participates in neutrophil-mediated myocardial damage by regulating the expression of P-selectin and ICAM-1 in ischemic and reperfused myocardium, and they also provide the basis for a novel therapeutic approach for the treatment of reperfusion injury.

Excessive stimulation of poly(ADP‐ribosyl)ation contributes to endothelial dysfunction in pre‐eclampsia

“…This attenuation has been mimicked in normal vessels by incubation with low levels of plasma from pre-eclamptic subjects (Ashworth et al, 1998;Hayman et al, 2000). Again we have reaffirmed this concept, but in these experiments we have reversed these detrimental effects by blocking the activity of PARP, an enzyme strongly linked with endothelial dysfunction in diabetes mellitus and other vascular conditions (Eliasson et al, 1997;Zingarelli et al, 1998;Soriano et al, 2001).…”

“…These factors, in addition to plasma tumour necrosis factor alpha (Conrad & Benyo, 1997;Anim-Nyame et al, 2003), are elevated in pre-eclampsia and, as such, could be an alternative stimulus for the PARP activation observed. A direct involvement of PARP in the regulation and expression of adhesion molecules in endothelial cells has also been defined (Zingarelli et al, 1998). Consequently, PARP could have an additional role in neutrophilendothelial interactions, promoting systemic inflammation, neutrophil respiratory burst and progression towards a hypercoagulatory state.…”

“…Consequently, poly(ADP-ribosyl)ation plays a key role in a number of physiological cellular functions including participation in DNA base-excision repair, resistance to genotoxic stress, regulation of genomic stability and gene expression, regulation of transcription and proteasomal function and apoptosis. However, in contrast to these cytoprotective functions, overstimulation of PARP is associated with pathophysiological effects resulting from rapid depletion of the intracellular NAD þ and ATP pools; this slows the rate of glycolysis and mitochondrial respiration and leads to cellular dysfunction (Eliasson et al, 1997;Szabo et al, 1997;Zingarelli et al, 1998;Burkart et al, 1999;Oliver et al, 1999;Pieper et al, 1999a, b;Soriano et al, 2001). PARP activation is implicated in the pathogenesis of stroke (Eliasson et al, 1997), autoimmune b-cell destruction (Burkart et al, 1999;Pieper et al, 1999a), shock and inflammation (Szabo et al, 1997;Oliver et al, 1999) and diabetic vascular dysfunction (Soriano et al, 2001).…”

The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

“…Another important function of the PARP enzyme is the regulation of the production of inflammatory mediators such as inducible nitric oxide synthase (iNOS), intercel-lular adhesion molecule-1 (ICAM-1) and major histocompatibility complex class II (MHC Class II) (Hiromatsu et al 1992, Ehrlich et al 1995, Szabó et al 1997b, Zingarelli et al 1998, Simbulan-Rosenthal et al 2000. NFkB is a key transcription factor in the regulation of this set of proteins and PARP has been shown can act as a coactivator in the NF-kB-mediated transcription.…”

“…On the other hand, overactivation of PARP represents an important mechanism of tissue damage in various pathological conditions associated with oxidative and nitrosative stress, including myocardial reperfusion injury (Zingarelli et al 1998), heart transplantation , heart failure (Pacher et al 2002b, c), stroke (Eliasson et al 1997), circulatory shock (Szabó et al 1997a, Oliver et al 1999, Jagtap et al 2002, Shimoda et al 2003, and autoimmune beta-cell destruction associated with diabetes mellitus (Burkart et al 1999, Pieper et al 1999. Activation of PARP and beneficial effects of various PARP inhibitors have been demonstrated in various forms of endothelial dysfunction such as the one associated with circulatory shock, hypertension, atherosclerosis, preeclampsia and aging (Szabó et al 1997, Hung et al 2002, Martinet et al 2002.…”