Genomes and Genes
Poly (ADP-Ribose) synthetase in expression of endothelia
Principal Investigator: Basilia Zingarelli
Abstract: Endothelial injury, and consequent adhesion of neutrophils to the vascular intima, is an early pathologic event in myocardial ischemia and reperfusion injury. The precise molecular mechanisms involved in neutrophil trafficking to injured tissue are not clear. Experimental evidence shows that oxidative stress is an important signal transduction event for the expression of endothelial adhesion molecules for leukocytes. In preliminary in vitro and in vivo studies we have found that oxidative stress causes cellular dysfunction and injury through a pathway mediated by the nuclear enzyme poly (ADP ribose) synthetase (PARS). In in vitro endothelial cells, peroxynitrite and hydrogen peroxide induce DNA single strand breaks and activate PARS, resulting in the depletion of cellular high-energy phosphates, cellular dysfunction and death. We have found that in vivo pharmacological or genetic inhibition of PARS reduces infract size and neutrophil accumulation into the injured tissue during myocardial ischemia and reperfusion in the rat and in the mouse. The present investigation is designed to evaluate the molecular basis of endothelial expressions of P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecular-1 (VCAM-1) induced by reperfusion-dependent oxidant stress, with special focus on the PARS pathway. The pathophysiological relevance of a PARS-mediated regulation of endothelial expression of adhesion molecules will be evaluated in in vivo experimental rodent models of myocardial ischemia and reperfusion injury. Specifically, experiments will be performed in a murine model of myocardial ischemia and reperfusion in knock-out animals lacking the gene of PARS and in littermate wild-type controls. For clinical relevance, the effect of pharmacological inhibition of PARS on endothelial injury and neutrophil accumulation will be studied in a rat model of myocardial reperfusion injury. Furthermore, experiments will be performed in cultured human umbilical vein endothelial cells subjected to oxidative and non oxidative stress. These in vitro experiments are proposed in order to obtain a more precise assessment of the role of intracellular PARS on the adult human endothelial dysfunction relevant to the human myocardial infarction. The results of the proposed project will provide important information on the role of PARS as a modulator of the endothelial barrier function and will contribute to the development of effective therapeutic interventions of cardiovascular diseases characterized by endothelial reperfusion injury.
Funding Period: 2000-03-17 - 2005-02-28
more information: NIH RePORT
- Inhibitors of poly (ADP-ribose) polymerase ameliorate myocardial reperfusion injury by modulation of activator protein-1 and neutrophil infiltrationJennifer Kaplan
Division of Critical Care Medicine, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
Shock 23:233-8. 2005..Our data demonstrate that inhibition of catalytic activity of PARP-1 may provide cardioprotection by regulating stress-induced signal transduction pathways...
- Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammationBasilia Zingarelli
Division of Critical Care Medicine, Cincinnati Children s Hospital Medical Center and the College of Medicine, University of Cincinnati, Cincinnati, Ohio 45229, USA
Shock 23:393-9. 2005....
- Diverse cardioprotective signaling mechanisms of peroxisome proliferator-activated receptor-gamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 and ciglitazone, in reperfusion injury: role of nuclear factor-kappaB, heat shock factor 1, and AktBasilia Zingarelli
Division of Critical Care Medicine, Cincinnati Children s Hospital Medical Center, The University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA
Shock 28:554-63. 2007..In contrast, GW-9662 did not affect the beneficial effects afforded by 15d-PGJ2. Thus, our data suggest that treatment with these chemically unrelated PPAR-gamma ligands results in diverse anti-inflammatory mechanisms...