Microsomal prostaglandin E2 synthase: A safer target than cyclooxygenases?

Molecular Interventions

Volumn 7, Issue 4, 2007, Pages 195-199

  Timmers, Leo ^a   Pasterkamp, Gerard ^a   De Kleijn, Dominique P V ^a,b  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^b ROYAL NETHERLANDS ACADEMY OF ARTS AND SCIENCES   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; CELECOXIB; CYCLOOXYGENASE 1; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITOR; DICLOFENAC; IBUPROFEN; MICROSOMAL PROSTAGLANDIN SYNTHASE 1 INHIBITOR; MICROSOMAL PROSTAGLANDIN SYNTHASE 2 INHIBITOR; NAPROXEN; NONSTEROID ANTIINFLAMMATORY AGENT; PLACEBO; PROSTAGLANDIN E2 SYNTHASE; PROSTAGLANDIN SYNTHASE; PROSTAGLANDIN SYNTHASE INHIBITOR; ROFECOXIB; UNCLASSIFIED DRUG; ISOMERASE; PROSTAGLANDIN; PROSTAGLANDIN E SYNTHASE;

CATALYSIS; CLINICAL TRIAL; DRUG EFFECT; DRUG EFFICACY; DRUG SAFETY; ENZYME ACTIVITY; ENZYME INHIBITION; GASTROINTESTINAL SYMPTOM; GENE DELETION; HEART INFARCTION; HUMAN; INFLAMMATION; LOW DRUG DOSE; MICROSOME; PAIN; PROTEIN EXPRESSION; REVIEW; STROKE; ARTICLE; CARDIOVASCULAR DISEASE; GENETICS; METABOLISM;

ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; CARDIOVASCULAR DISEASES; CYCLOOXYGENASE INHIBITORS; HUMANS; INFLAMMATION; INTRAMOLECULAR OXIDOREDUCTASES; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES; PROSTAGLANDINS;

EID: 34548795534     PISSN: 15340384     EISSN: 15432548     Source Type: Journal    
DOI: 10.1124/mi.7.4.5     Document Type: Review

References (23)

1. Bombardier, C., Laine, L., Reicin, A. et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N. Engl. J. Med. 343, 1520-1528 (2000). This trial proved superiority of rofecoxib (COX-2 inhibitor) over naproxen (tNSAID) regarding gastrointestinal complications, and shifted worldwide NSAID prescription behavior towards selective COX-2 inhibitors.
2. Silverstein, F.E., Faich, G., Goldstein, J.L. et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 284, 1247-1255 (2000). In this clinical trial, celecoxib was demonstrated to have reduced gastrointestinal risk compared to ibuprofen and diclofenac.
3. Hrachovec, J.B. and Mora, M. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. JAMA 286, 2398 (2001).
4. Bresalier, R.S., Sandler, R.S., Quan, H. et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N. Engl. J. Med. 352, 1092-1102 (2005). This is the first trial linking COX-2 inhibition with increased cardiovascular risk in patients and led to the withdrawal of rofecoxib from the market.
5. Solomon, S.D., McMurray, J.J., Pfeffer, M.A. et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl. J. Med. 352, 1071-1080 (2005). With this trial, a second COX-2 inhibitor next to rofecoxib, celecoxib, became suspect for increased cardiovascular risk, suggesting a class-wide effect.
6. McGettigan, P. and Henry, D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 296, 1633-1644 (2006). This systematic review nicely overviews cardiovascular risk of the most important NSAIDs.
7. Timmers, L., Sluijter, J.P., Verlaan, C.W. et al. Cyclooxygenase-2 inhibition increases mortality, enhances left ventricular remodeling, and impairs systolic function after myocardial infarction in the pig. Circulation 115, 326-332 (2007). From this study it became evident that selective COX-2 inhibition enhances heart failure following myocardial infarction, providing additional motivation to be cautious with coxibs in cardiovascular risk patients.
8. Hippisley-Cox, J. and Coupland, C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 330, 1366 (2005).
9. Watson, D.J., Rhodes, T., Cai, B., and Guess, H.A. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch. Intern. Med. 162, 1105-1110 (2002).
10. Farkouh, M.E., Kirshner, H., Harrington, R.A. et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: Randomised controlled trial. Lancet 364, 675-684 (2004).
11. Grosser, T., Fries, S., and FitzGerald, G.A. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J. Clin. Invest. 116, 4-15 (2006). This paper describes the biological mechanism for increased cardiovascular risk with COX-2 inhibition and touches upon potential clinical implications.
12. Cheng, Y., Wang, M., Yu, Y., Lawson, J., Funk, C.D., and Fitzgerald, GA. Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function. J. Clin. Invest. 116, 1391-1399 (2006). The authors provide a potential alternative anti-inflammatory target for cyclooxygenases with reduced cardiovascular risk in murine models.
13. Johnson, A.G., Nguyen, T.V., and Day, R.O. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann. Intern. Med. 121, 289-300 (1994).
14. Aw, T.J., Haas, S.J., Liew, D. and, Krum, H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch. Intern. Med. 165, 490-496 (2005).
15. MacMahon, S., Peto, R., Cutler, J. et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 335, 765-774 (1990).
16. Cheng, H.F. and Harris, R.C. Cyclooxygenases, the kidney, and hypertension. Hypertension 43, 525-530 (2004).
17. 2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. J. Biol. Chem. 278, 37937-37947 (2003).
18. Jakobsson, P.J., Thoren, S., Morgenstern, R., and Samuelsson, B.. Identification of human prostaglandin E synthase: A microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc. Natl. Acad. Sci. U.S.A. 96, 7220-7225 (1999). In this study mPGES-1 was first identified as a potential novel target for drug development.
19. Trebino, C.E., Stock, J.L., Gibbons, C.P. et al. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc. Natl. Acad. Sci. U S A. 100, 9044-9049 (2003). In this article, the authors demonstrate similar anti-inflammatory potential and pain relief with mPGES-1 knock out compared to NSAID administration.
20. Jia, Z., Zhang, A., Zhang, H., Dong, Z., and Yang, T. Deletion of microsomal prostaglandin E synthase-1 increases sensitivity to salt loading and angiotensin II infusion. Circ. Res. 99, 1243-1251 (2006).
21. Kamei, D., Yamakawa, K., Takegoshi, Y. et al. Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin e synthase-1. J. Biol. Chem. 279, 33684-33695 (2004).
22. 2 synthase that acts in concert with cyclooxygenase-2. J. Biol. Chem. 275, 32783-32792 (2000).
23. Stichtenoth, D.O., Thorén, S., Bian, Peters-Golden, M., Jakobsson, P.J., and Crofford, L.J. Microsomal prostaglandin E synthase is regulated by proinflammatory cytokines and glucocorticoids in primary rheumatoid synovial cells. J. Immunol. 167, 469-474 (2001).