LETTERS TO THE EDITOR
Cyclooxygenase-2 in myocardial ischemia
is it really a friend? Reply
Roberto Bolli, MD*
* Division of Cardiology, ACB, Third Floor, 550 South Jackson Street, University of Louisville, Louisville, KY 40292, USA
Ken Shinmura, MD, PhD*
rbolli{at}louisville.edu
We welcome the chance to reply to the letter of Dr. Abbate and colleagues, as this gives us an opportunity to rectify a number of common misconceptions. First, the assertion by Dr. Abbate and colleagues that (following myocardial ischemia/reperfusion) "the majority of myocardiocytes are lost through apoptosis" is not supported by any evidence. Whereas apoptosis does occur after acute myocardial ischemia and reperfusion (1), the quantitative aspects of this process remain controversial and, at best, speculative. Regardless, measurements of infarct size at 72 h after reperfusion (as done by Shinmura et al. [2]) would include both necrotic and apoptotic cell death. It is also incorrect to state that apoptosis might be enhanced by late preconditioning—again, no evidence exists to support this assertion. On the contrary, late preconditioning produces a marked reduction in infarct size (3). There is also no evidence to support the suggestion by Dr. Abbate and colleagues that reducing stunning is not beneficial; 20 years of research have shown that myocardial stunning is an unnecessary manifestation of reperfusion injury, which can be minimized without adverse consequences (4). The antistunning effects of late preconditioning (3) are associated with sustained improvement in left ventricular (LV) function (5).
Similarly, the statement by Dr. Abbate and colleagues that "COX-2 [cyclooxygenase-2] is a mediator of ischemic damage" is not supported by the available evidence. The study by Takadera et al. (6) dealt with PGE2 (rather than COX-2 per se) and examined brain injury rather than cardiac injury. Apparently the abstract cited by Dr. Abbate and colleagues (which is not available at the time of this writing) showed an association between COX-2 expression and apoptosis; this association does not in any way indicate a cause-and-effect relationship. Saito et al. (7) assessed LV function (not infarct size) at four weeks after permanent occlusion (not after transient occlusion followed by reperfusion). Their study examined the role of COX-2 in LV remodeling, which is completely different from the role of COX-2 in limiting acute ischemia/reperfusion injury; the two issues should not be confused. The second study by Saito et al. (8) also examined a permanent coronary occlusion (without reperfusion) and did not measure infarct size as a percent of the risk region. Contrary to the statements by Dr. Abbate and colleagues, considerable evidence indicates that COX-2 by-products (particularly prostacyclin) exert antiapoptotic actions (9). The abstract by Iwai-Kanai et al. (10) examined apoptosis induced in vitro by isoproterenol or H2O2 (not by ischemia) in neonatal (not adult) cardiac myocytes. There is no evidence that aspirin acted by inhibiting COX-2 or that the model used in that study (10) has anything to do with myocardial ischemia/reperfusion. Although COX-2 has been reported to mediate apoptosis in Gh transgenic mice (11), this is not a setting relevant to myocardial ischemia/reperfusion injury, and the investigators indicated that the actions of COX-2 are complex (11).
In August 2000, we demonstrated, for the first time, that COX-2 is a cardioprotective protein that alleviates both myocardial stunning and infarction (2). We have subsequently reviewed the mounting evidence for a protective role of COX-2 (9). Three years have passed and increasing evidence supports our hypothesis. Cyclooxygenase-2 protects isolated myocytes from oxidative stress (12), and COX-2 inhibitors aggravate doxorubicin-mediated injury (13). Targeted disruption of the COX-2 gene results in myocardial fibrosis (14). Myocardial ischemia/reperfusion injury is exacerbated in COX-2 null mice (15), implying that constitutively expressed COX-2 is cardioprotective. Moreover, PGI2 is a potent cytoprotective prostanoid (9), and COX-2 has been found to be the major source of systemic biosynthesis of PGI2 in healthy volunteers (16) and in patients with atherosclerosis (17).
As elaborated elsewhere (9), the concept that COX-2 is deleterious during acute myocardial ischemia is a common misconception. We propose that the biological effects of COX-2 may differ depending on the cellular type(s) where it is expressed (e.g., vascular wall vs. cardiac myocytes), the pathophysiological setting, and the ability of cells to metabolize COX-2-derived PGH2 into cytoprotective prostanoids.
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References
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1. Kajstura J, Cheng W, Reiss K, et al. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest. 1996;74:86–107[Medline]
2. Shinmura K, Tang X-L, Wang Y, et al. Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci U S A. 2000;97:10197–10202[Abstract/Free Full Text]
3. Bolli R. The late phase of preconditioning. Circ Res. 2000;87:972–983[Abstract/Free Full Text]
4. Bolli R. Myocardial "stunning" 20 years later: a summary of current concepts regarding its pathophysiology, pathogenesis, and clinical significance. Dialog Cardiovasc Med. 1996;1:5–26
5. Takano H, Tang X-L, Bolli R. Late preconditioning enhances recovery of myocardial function after infarction in conscious rabbits. Am J Physiol. 2000;279:H2372–H2381
6. Takadera T, Yumoto H, Tozuka Y, Ohyashiki T. Prostaglandin E(2) induces caspase-dependent apoptosis in rat cortical cells. Neurosci Lett. 2002;317:61–64[CrossRef][Medline]
7. 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]
8. 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]
9. Bolli R, Shinmura K, Tang XL, et al. Discovery of a new function of cyclooxygenase (COX-2). COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res. 2002;55:506–519[Abstract/Free Full Text]
10. Iwai-Kanai E, Yanazume T, Oda T, et al. Aspirin protects cardiac myocytes from apoptosis by modulating mitogen-activating protein kinases. J Am Coll Cardiol. 2003;41(Suppl A):313A (abstr)
11. 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]
12. Adderley SR, Fitzgerald DJ. Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2. J Biol Chem. 1999;274:5038–5046[Abstract/Free Full Text]
13. Dowd NP, Scully M, Adderley SR, Cunningham AJ, Fitzgerald DJ. Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo. J Clin Invest. 2001;108:585–590[CrossRef][Medline]
14. Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature. 1995;378:406–409[CrossRef][Medline]
15. Camitta MG, Gabel SA, Chulada P, et al. Cyclooxygenase-1 and -2 knockout mice demonstrate increased cardiac ischemia/reperfusion injury but are protected by acute preconditioning. Circulation. 2001;104:2453–2458[Abstract/Free Full Text]
16. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999;96:272–277[Abstract/Free Full Text]
17. Belton O, Byrne D, Kearney D, Leahy A, Fitzgerald DJ. Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation. 2000;102:840–845[Abstract/Free Full Text]
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