Ann Thorac Surg 2002;73:581
© 2002 The Society of Thoracic Surgeons
Invited commentary
Ari O. Halldorsson, MDa
a Division of Cardiothoracic Surgery, Texas Tech University Health Sciences Center, 3601 4th St, Suite 3A111, Lubbock, TX 79430, USA
e-mail: ari.halldorsson{at}ttmc.ttuhsc.edu
This article describes a very well conducted animal study on the protective effects of a new poly (ADP-ribose) synthetase (PARS) inhibitor, PJ34, during myocardial ischemia and reperfusion injury. Dr Faro and coauthors can be congratulated on an excellent study using state of the art cardiovascular modalities and an equally well written manuscript. This study shows without a doubt that PARS inhibitors play a significant role in cell injury following ischemia-reperfusion and clinical studies are indicated following the excellent outcome of this experiment.
Poly (ADP-ribrose) synthetase is a nuclear enzyme that has been extensively investigated. It has been long known that PARS plays a significant role in apoptosis, but the exact mechanism by which it causes cell death, cellular differentiation, malignant transformation, gene amplification, and DNA replication is still being heavily investigated. During the 1970s and 1980s PARS received tremendous attention and it was found that PARS activation leads to NAD+ overuse that eventually causes intracellular ATP depletion. Glycolysis and mitochondrial respiration subside leading to necrotic type of cell death. Researchers interest in PARS’s role in this suicidal cell death gained new momentum in the mid-nineties when it was found that nitrous oxide, produced from L-Arginine by nitrous oxide synthetase, was an important mediator in inflammatory and ischemia-reperfusion injury and that PARS activation played a significant role in that cascade. It is equally important from a research standpoint that PARS inhibitors are available making it easier to delineate the physiologic role of PARS. The three most common are nicotinamide, 3-aminobenzamine, and benzamine. It has been proven without a doubt that DNA single-strand break is the most likely activator of PARS during ischemia-reperfusion. It is not known whether a massive single DNA strand break activates the system by itself, or whether a minor injury initiates a self-sustaining cascade, which could include neutrophil activation, adhesion molecules up-regulation or yet an unknown positive "feed-forward" cycle that results in slow apoptosis. Although, there seems no doubt that PARS plays an important role in caspase-3 mediated apoptotic cell death, several researchers have noted that this process is too slow to explain the necrotic cell death that occurs during ischemia-reperfusion. Energy is depleted early in ischemia-reperfusion injury making it unlikely that energy consuming process like apoptosis can occur. Based on these findings many feel that PARS plays more of a role as a facilitator of oxygen free radicals, oxidant induced cell necrosis, and leukocyte induced injury. It is somewhat surprising that PARS has not been deleted during the evolutionary process because of its significant suicidal effects. Some scientists have postulated that PARS plays more of a role in DNA maintenance and repair than previously thought. On the other hand it does not seem to be necessary for normal development, since three recently developed PARS "knockout" animal models have all been morphologically and physiologically normal and viable. These "knock out" models are going to be invaluable in evaluating the short and long term effect of PARS inhibition.
Although, the natural and pathological function of PARS is still being evaluated and many aspects of this fascinating enzyme are unknown, this study and others show that inhibiting its function plays a significant role in decreasing ischemia-reperfusion injury in the myocardium. This new PARS inhibitor, PJ34, has the advantage of being more potent than the ones previously used and have been thoroughly investigated in both cell free PARS assays and cell cultures. This study also shows nicely that this PARS inhibitor causes complete enzyme inhibition. Therefore, making it more unlikely that the infarct size can be suppressed more than 30% with higher dosage or different inhibitor. If PJ34 performs as well in human studies as in animals without any unforeseen complications, we can expect a one-third decrease in infarct size. Using PARS inhibitors does not prevent us from blocking other "down stream"processes initiated by free radical bursts during reperfusion , thereby decreasing the infarct size even further. Also of interest is that several studies have shown that PARS activation after ischemia-reperfusion in the myocardium is prolonged making it possible to get positive effects from giving PARS inhibitors like PJ34 even several hours after the initial ischemic event. This study has opened the doors to human studies into the effect of PARS inhibitors after ischemia-reperfusion.
Related Article
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Myocardial protection by PJ34, a novel potent poly (ADP-ribose) synthetase inhibitor
- Renato Faro, Yoshiya Toyoda, James D. McCully, Prakash Jagtap, Eva Szabo, Laszlo Virag, Cesario Bianchi, Sidney Levitsky, Csaba Szabo, and Frank W. Sellke
Ann. Thorac. Surg. 2002 73: 575-581.
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