J Thorac Cardiovasc Surg 2004;128:323-324
© 2004 The American Association for Thoracic Surgery
Poly–adenosine diphosphate–ribose polymerase inhibition for myocardial protection: Pathophysiologic and physiologic considerations
Wilhelm Bloch, PhDa,
Uwe Mehlhorn, MDb
a Institute I for Anatomy, University of Cologne, Cologne, Germany
b Department of Cardiothoracic Surgery, University of Cologne, Cologne, Germany
To the Editor:
We read with great interest the article by Szabo and associates1 in which they reported the use of state-of-the-art animal instrumentation and molecular biologic techniques to demonstrate that poly–adenosine diphosphate–ribose polymerase (PARP) inhibition protects against myocardial and endothelial reperfusion injury after crystalloid cardioplegic arrest. In the discussion, they attributed this primarily to energy-saving effects, because activation and (more importantly) activity of the enzyme PARP require energy.1 However, they did not address the physiologic functions of PARP in repairing DNA breaks, especially after DNA cleavage by caspases as part of the apoptotic cascade, a genetically programmed process for the death and subsequent removal of injured cells.2 Recent studies have shown that cardioplegic arrest induces the apoptosis signal cascade in cardiac myocytes and endothelial cells,3,4 so inhibition of the repair enzyme PARP—even though energy sparing—may result in higher numbers of cardiac myocytes completing apoptosis, thus abolishing any potential positive short-term effects attributable to PARP inhibition.
Considering that the benefit of energy sparing by PARP inhibition is necrosis avoidance,5 the therapeutic concept of PARP inhibition can only be effective if the unprotected ischemia/reperfusion injury leads to necrosis, such as in myocardial infarction or stroke. If, however, PARP activation does not lead to cellular oxidized nicotinamide adenine dinucleotide (NAD+) depletion by more than 75%,5 as has recently been demonstrated in transient global cerebral ischemia, PARP inhibition decreases the number of surviving cells.6 These data suggest that in the absence of NAD+ depletion as induced by mild ischemia-reperfusion injury (protected ischemia such as cardioplegic arrest) PARP activation would be protective. Therefore, the therapeutic use of PARP inhibitors should be critically proved with respect to the degree of injury. Finally, it must be questioned whether inhibition or scavenging of upstream effectors of apoptosis, such as reactive oxygen species, would be more effective through reduction of endogenous PARP activation parallel to the inhibition of DNA damage and subsequent apoptosis. A study comparing inhibition of upstream activators of ischemia-reperfusion injury (reactive oxygen species scavengers) versus PARP inhibition appears appropriate. Further issues that need to be addressed before therapeutic PARP inhibition are the various other physiologic functions of activated PARP, including transcriptional regulation, stimulation of nuclear proteasomal function, and its antiaging effect.2 Certainly, these aspects are beyond the scope of the study of Szabo and associates; however, they should have been mentioned.
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References
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- Szabo G, Buhmann V, Andrasi T, Stumpf N, Bahrle S, Kekesi V, et al. Poly-ADP-ribose polymerase inhibition protects against myocardial and endothelial reperfusion injury after hypothermic cardiac arrest. J Thorac Cardiovasc Surg. 2003;126:651–658[Abstract/Free Full Text]
- Burkle A. Physiology and pathophysiology of poly(ADP-ribosyl)ation. Bioessays. 2001;23:795–806[Medline]
- Fischer UM, Klass O, Stock U, Easo J, Geissler HJ, Fischer JH, et al. Cardioplegic arrest induces apoptosis signal-pathway in myocardial endothelial cells and cardiac myocytes. Eur J Cardiothorac Surg. 2003;23:984–990[Abstract/Free Full Text]
- Schmitt JP, Schroder J, Schunkert H, Birnbaum DE, Aebert H. Role of apoptosis in myocardial stunning after open heart surgery. Ann Thorac Surg. 2002;73:1229–1235[Abstract/Free Full Text]
- Shall S, de Murcia G. Poly(ADP-ribose) polymerase-1: what have we learned from the deficient mouse model? Mutat Res. 2000;460:1–15[Medline]
- Nagayama T, Simon RP, Chen D, Henshall DC, Pei W, Stetler RA, et al. Activation of poly(ADP-ribose) polymerase in the rat hippocampus may contribute to cellular recovery following sublethal transient global ischemia. J Neurochem. 2000;74:1636–1645[Medline]
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