LETTERS TO THE EDITOR
Cyclooxygenase-2 in myocardial ischemia
is it really a friend?
Antonio Abbate, MD*,
Giuseppe G. L. Biondi-Zoccai, MD*,
Antonio Maria Leone, MD*,
Alfonso Baldi, MD* and
Filippo Crea, MD, FACC*
* Institute of Cardiology, Catholic University, Largo A. Gemelli, 8, 00168 Rome, Italy
abbatea{at}yahoo.com
We read with interest the elegant experimental study performed by Shinmura et al. (1) and published in the Journal showing that cyclooxygenase-2 (COX-2) inhibition prevents delayed ischemic preconditioning and, in particular, reduction in postischemic stunning. However, we believe it is unlikely that their experimental findings have relevant clinical implications, as repeatedly suggested by the investigators. Ischemic preconditioning has been shown to reduce infarct size and myocardial stunning. However, the assessment of infarct size is probably more complex than believed a few years ago. Indeed, the majority of myocardiocytes are lost through apoptosis (2,3), which is not assessed by standard techniques, rather than through necrosis as previously thought. Therefore, if assessment of infarct size is based solely on enzyme leakage and/or on the extent of necrosis and fibrosis at pathology it does not reflect total effective myocardiocyte loss. Notably, classic studies on the effects of preconditioning on infarct size did not take into account cell apoptosis, which might even be enhanced by early or late ischemic preconditioning (2,4). Moreover, ischemic preconditioning-induced reduction in stunning does not necessarily have to be considered beneficial. The ischemic cell undergoes both short- and long-term modifications to confront hypoxia, in a delicate balance between survival and death (5,6). Stunning and hibernation are natural responses to ischemia and are probably part of the cellular mechanisms of adaptation aimed toward programmed cell survival after ischemia (5,6), whereas prolonged ischemia (either with or without reperfusion) causes cell death.
Finally, and most importantly, recent data indicate that COX-2 is a mediator of ischemic damage. Takadera et al. (7) have shown that COX-2 plays a key role in central nervous system apoptosis. We have recently found that COX-2 expression in recent myocardial infarction (MI) is associated with higher apoptotic rates (8); Saito et al. (9,10), using an experimental model of MI, have reported beneficial effects, in terms of postinfarction dysfunction, of COX-2 inhibitors, and just recently high-dose aspirin was found to protect myocardiocytes from apoptosis (11). Of note, in a different experimental setting, Zhang et al. (12) found an increase of COX-2 activity in genetically engineered animals prone to heart failure, and, most interestingly, they describe beneficial effects of selective COX-2 inhibition.
In conclusion, though COX-2 may provide a friendly protection to ischemic myocardiocytes, as suggested by Shinmura and colleagues (1), evidence is still too scant to scientifically discard its potential role as a foe leading to unfavorable outcomes in the process of cardiac adaptation to ischemia. The present study by Shinmura et al. (1) convincingly shows that COX-2 plays an active role in myocardial response to ischemia and that inhibition of COX-2 significantly affects the course of events after ischemic insults. Whether the effect of COX-2 is beneficial or deleterious in the clinical setting cannot be drawn from current data. Thus, the statement that COX-2 inhibitors should be used with caution because they may deprive the heart of its innate defensive response is completely speculative to date as further studies are needed, and COX-2 may ultimately be found to be more a "foe" than a "friend."
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References
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1. Shinmura K, Modani E, Xuan YT, Dawn B, Tang XL, Bolli R. Effects of aspirin on late preconditioning against myocardial stunning in conscious rabbits. J Am Coll Cardiol. 2003;41:1183–1194[Abstract/Free Full Text]
2. James TN. Homage to James B. Herrick: a contemporary look at myocardial infarction and at sickle-cell heart disease. Circulation. 2000;101:1874–1887[Free Full Text]
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8. Abbate A, Biondi-Zoccai GGL, Santini D, et al. Cyclooxygenase-2 (COX-2) expression at site of recent myocardial infarction: friend or foe (abstr)? Eur J Heart Fail 2003;2:140
9. Saito T, Rodger IW, Hu F, Shennib H, Giaid A. Inhibition of cyclooxygenase-2 improves cardiac function in myocardial infarction. Biochem Biophys Res Commun. 2000;273:772–775[CrossRef][Medline]
10. Saito T, Rodger IW, Shennib H, Hu F, Tayara L, Giaid A. Cyclooxygenase-2 (COX-2) in acute myocardial infarction: cellular expression and use of selective COX-2 inhibitor. Can J Physiol Pharmacol. 2003;81:114–119[CrossRef][Medline]
11. Iwai-Kanai E, Yanazume T, Oda T, et al. Aspirin protects cardiac myocytes from apoptosis by modulating mitogen-activating protein kinases (abstr). J Am Coll Cardiol. 2003;41(Suppl A):313A
12. Zhang Z, Vezza R, Plappert T, et al. COX-2-dependent cardiac failure in Gh/tTG transgenic mice. Circ Res. 2003;92:1153–1161[Abstract/Free Full Text]
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