EDITORIAL

European Heart Journal (2014) 35, 2208–2210 doi:10.1093/eurheartj/ehu219

Cyclooxygenase-2 polymorphism: another piece in the cardiovascular puzzle Francesco Cipollone* and Donato Santovito Clinica Geriatrica e Centro di Eccellenza Europeo e di Riferimento Regionale per l’Aterosclerosi, l’Ipertensione Arteriosa e le Dislipidemie, Nuovo Policlinico ‘SS. Annunziata’, Universita` ‘G. d’Annunzio’, Via dei Vestini 66, 66100 Chieti (CH), Italy Online publish-ahead-of-print 4 June 2014

Prostaglandin–endoperoxidase synthases, commonly referred as cyclooxygenases (COX), are key enzymes in the metabolism of arachidonic acid because they lead to the production of prostaglandins (PGs). These molecules are critically involved in key biological processes, including inflammation, blood clotting, and vascular homeostasis. Two main isoforms of cyclooxygenases have been described, named COX-1 and COX-2, which are encoded by two separated genes. In particular, COX-1 is encoded by a gene mapped to chromosome 9q32-q33.3 and is constitutively expressed in many tissues. In contrast, COX-2 is encoded by a gene mapped to chromosome 1q25.2-q25.3 and its expression is induced by pro-inflammatory stimuli. The role of COX-2 in atherosclerosis and cardiovascular diseases has been thoroughly investigated in both pre-clinical and clinical settings. It has been shown that COX-2 expression is increased in response to several pro-atherosclerotic stimuli (i.e. angiotensin II, oxidized low-density lipoprotein) and is evident in animal and human atherosclerotic plaques.1 – 4 Interestingly, COX-2 (as well as COX-1) catalyses the biosynthesis of prostaglandin H2 (PGH2), a highly unstable molecule, which is further metabolized by other enzymes to produce different series of prostaglandins and thromboxane. Although every cell may produce PGH2, only one or two final eicosanoids tend to be prevalent for a specific cell type, owing to the differential expression of downstream enzymes. In particular, in macrophages COX-2 is functionally coupled with type 1 microsomial PG synthase (mPGES-1), leading to the formation of prostaglandin E2 (PGE2), which, by interacting with the E-prostanoid receptor-4, promotes detrimental effects on atherosclerotic plaque stability, including the increased expression and lytic activity of matrix metalloproteinases-2 and -9.1,5 Furthermore, in vascular smooth muscle cells the functionally coupled enzymes COX-2 and

mPGES-1 lead to the production of PGE2, which interacts with the E-prostanoid receptor-3, promoting vascular smooth muscle cell proliferation and neointima formation in mice.6 Conversely, in endothelial cells (ECs) COX-2 is a major contributor to prostacyclin production in vivo, which promotes protective effects against atherosclerosis and thrombosis.7 Thus, the ultimate effects of COX-2 and the consequences of its therapeutic inhibition are mainly a function of the cell source of that enzyme. Indeed, although the selective deletion of COX-2 in macrophages results in beneficial effects on atherosclerosis progression in mice,8 COX-2 deletion in ECs impairs vascular function and predisposes to thrombosis in both microvasculature and large vessels.9 The clinical relevance of these findings is highlighted by the controversial results in terms of cardiovascular events in patients undergoing prolonged treatment with selective COX-2 inhibitors (so-called ‘coxibs saga’). Interestingly, genome analysis showed that several singlenucleotide polymorphisms (SNPs) might affect the COX-2 gene sequence (over 500 active SNPs for human COX-2 are enlisted in single nucelotide polymorphism database). Most of these are intronic or synonymous changes, thus functional relevance is unlikely. However, some of them have been shown to have a potential biological (and clinical) relevance by effectively influencing gene expression. In particular, the rs20417 polymorphism involves the COX-2 promoter with a guanine-to-cytosine substitution at position 2 765 ( 2 765G  C) within a putative binding site for the transcriptional factor Sp1 (a positive inducer of COX-2 transcription), and therefore results in a reduced promoter activity.10,11 Notably, patients undergoing elective coronary bypass surgery carrying the 2 765C allele had significantly lower levels of C-reactive protein.10 Moreover, in a prospective matched case –control study we have shown that the prevalence of the – 765C allele, both in homozygosity and in heterozygosity, was significantly higher in patients with acute ischaemic stroke or myocardial infarction when compared with control subjects.11 However, since these first

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. † doi:10.1093/eurheartj/ehu168.

* Corresponding author. Clinica Geriatrica e Centro di Eccellenza Europeo e di Riferimento Regionale per l’Aterosclerosi, l’Ipertensione Arteriosa e le Dislipidemie, Nuovo Policlinico ‘SS. Annunziata’, Universita` ‘G. d’Annunzio’, Via dei Vestini 66, 66100 Chieti (CH), Italy. Tel: +39 085 9172272, Fax: +39 085 9172272, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].

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This editorial refers to ‘Association of cyclooxygenase-2 genetic variant with cardiovascular disease’†, by S. Ross et al., on page 2242.

Editorial

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reports, other studies have investigated the impact of this functional polymorphism on the cardiovascular risk, often providing fairly controversial results, mainly as consequence of underpowered sample sizes or heterogeneity in the populations studied. In this issue of the European Heart Journal, Ross et al. 12 report the results of a large meta-analysis of 49 232 patients who were participants in six large prospective multicentre randomized clinical trials in the cardiovascular area. In particular, the authors had access to data of patients enrolled in the trials ACTIVE-A (1061 subjects), CURE (4662 subjects), DREAM (14 104 subjects), ONTARGET (3610 subjects), RE-LY (2501 subjects), and Women’s Health Study (23 294 subjects). Overall, they found that subjects carrying the 2 765C allele showed a reduced risk of cumulative major cardiovascular outcomes [odds ratio (OR), 0.78; 95% confidence interval (CI), 0.70–0.87], vascular death (OR, 0.76; 95% CI, 0.63–0.90), myocardial infarction (OR, 0.78; 95% CI, 0.67– 0.92), and stroke (OR, 0.83; 95% CI, 0.70–1.00). Notably, a subgroup analysis performed to explore whether specific cardiovascular risk factors may modify the association between the –765C allele and cardiovascular outcomes showed that none of the major cardiovascular risk factor has a significant impact. The association between COX-2 rs204417 polymorphism and cardiovascular risk factors was also explored by analysing the data from the additional population of the INTERHEART study. Although only a weak association between rs20417 polymorphism and cardiovascular outcomes was found using an additive genetic model (OR, 0.92; 95% CI, 0.85 –0.99), overall results confirmed no significant interactions with major cardiovascular risk factors (hypertension, diabetes, obesity, apolipoprotein B, and smoking habits), with the only exception being a marginal interaction with apolipoprotein A1. Finally, the authors also provide a

demonstration of the inhibitory effect of the polymorphism on COX activity by showing that 2 765C allele carriers have lower urinary levels of both 11-dehydro- thromboxane B2 and 2,3-dinor-6-keto prostaglandin F1a, two main metabolites of thromboxane A2 and prostacyclin, respectively.7,9,13 The study by Ross and colleagues is remarkable because of the large population analysed, the accurate statistical approach, which allows exclusion of potential interactions with aspirin treatment, and for having excluded deviation from the Hardy-Weinberg equilibrium in each ethnic group for each study thus reducing the chance of false positives. Nevertheless, some limitations should be taken into account when reading the paper. Firstly, the nature of the study (a meta-analysis) includes clear limitations, such as the heterogeneity between study populations, trial outcomes, and pharmacological treatments. Secondly, the populations enrolled in two trials (RE-LY and ONTARGET) were not genotyped, and a proxy was used instead. This may explain the lower prevalence of the minor allele carriers in these studies and may represent a potential bias. Finally, the reduced levels of urinary prostacyclin metabolites found in this study might suggest a slight reduction of COX-2 activities also in ECs, which are the main source of protective prostacyclin.7,9 Thus, other determinants, apart from macrophage-specific inhibition of COX-2 activity, might also contribute to the protective effects of the –765C allele. Future experimental studies will help to clarify these aspects definitively. In conclusion, for the rs20417 polymorphism as well as for many other polymorphisms discovered, any consequences in daily clinical practice are probably still a long way off. Nevertheless, the findings reported in this article represent an attractive starting point for future research aiming to understand fully the intimate mechanisms

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Figure 1 Role of cyclooxygenase-2 in the different vascular cell types.

2210 of COX regulation in vascular cells and their crucial role in atherothrombosis in humans. Conflict of interest: none declared.

References

7. Capone ML, Tacconelli S, Sciulli MG, Grana M, Ricciotti E, Minuz P, Di Gregorio P, Merciaro G, Patrono C, Patrignani P. Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation 2004;109:1468 –1471. 8. Hui Y, Ricciotti E, Crichton I, Yu Z, Wang D, Stubbe J, Wang M, Pure´ E, FitzGerald GA. Targeted deletions of cyclooxygenase-2 and atherogenesis in mice. Circulation 2010;121:2654 –2660. 9. Yu Y, Ricciotti E, Scalia R, Tang SY, Grant G, Yu Z, Landesberg G, Crichton I, Wu W, Pure´ E, Funk CD, FitzGerald GA. Vascular COX-2 modulates blood pressure and thrombosis in mice. Sci Transl Med 2012;4:132ra54. 10. Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, Humphries SE, Laurent GJ. Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol 2002;22:1631 –1636. 11. Cipollone F, Toniato E, Martinotti S, Fazia M, Iezzi A, Cuccurullo C, Pini B, Ursi S, Vitullo G, Averna M, Arca M, Montali A, Campagna F, Ucchino S, Spigonardo F, Taddei S, Virdis A, Ciabattoni G, Notarbartolo A, Cuccurullo F, Mezzetti A. A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. JAMA 2004;291: 2221 –2228. 12. Ross S, Eikelboom J, Anand SS, Eriksson N, Gerstein HC, Mehta S, Connolly SJ, Rose L, Ridker PM, Wallentin L, Chasman DI, Yusuf S, Pare G. Association of cyclooxygenase-2 genetic variant with cardiovascular disease. Eur Heart J 2014;35: 2242 –2248. 13. Ferroni P, Riondino S, Vazzana N, Santoro N, Guadagni F, Davı` G. Biomarkers of platelet activation in acute coronary syndromes. Thromb Haemost 2012;108: 1109 –1123.

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1. Cipollone F, Prontera C, Pini B, Marini M, Fazia ML, De Cesare D, Iezzi A, Ucchino S, Boccoli G, Saba V, Chiarelli F, Cuccurullo F, Mezzetti A. Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E2-dependent plaque instability. Circulation 2001;104:921 –927. 2. Burleigh ME, Babaev VR, Oates JA, Harris RC, Gautam S, Riendeau D, Marnett LJ, Morrow JD, Fazio S, Linton MF. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation 2002;105:1816 – 1823. 3. Grosser T, Yu Y, FitzGerald GA. Emotion recollected in tranquility: lessons learned from the COX-2 saga. Annu Rev Med 2010;61:17 –33. 4. Santovito D, Mezzetti A, Cipollone F. Cyclooxygenase and prostaglandin synthases: roles in plaque stability and instability in humans. Curr Opin Lipidol 2009;20:402 –408. 5. Cipollone F, Fazia ML, Iezzi A, Cuccurullo C, De Cesare D, Ucchino S, Spigonardo F, Marchetti A, Buttitta F, Paloscia L, Mascellanti M, Cuccurullo F, Mezzetti A. Association between prostaglandin E receptor subtype EP4 overexpression and unstable phenotype in atherosclerotic plaques in human. Arterioscler Thromb Vasc Biol 2005;25:1925–1931. 6. Zhang J, Zou F, Tang J, Zhang Q, Gong Y, Wang Q, Shen Y, Xiong L, Breyer RM, Lazarus M, Funk CD, Yu Y. Cyclooxygenase-2-derived prostaglandin E2; promotes injury-induced vascular neointimal hyperplasia through the E-prostanoid 3 receptor. Circ Res 2013;113:104 –114.

Editorial

Cyclooxygenase-2 polymorphism: another piece in the cardiovascular puzzle.

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