• 四川大學(xué)華西醫(yī)院藥劑科（成都，610041）;

【摘要】　 環(huán)氧化酶（cycloxygenase，COX）有兩種異構(gòu)酶，COX-1對(duì)機(jī)體起生理性保護(hù)作用；COX-2參與炎癥等病理作用調(diào)節(jié)。非甾體類藥物抗炎鎮(zhèn)痛作用源于對(duì)COX-2的抑制，而胃腸道等不良反應(yīng)的發(fā)生則與COX-1被抑制密切相關(guān)。近年研究發(fā)現(xiàn)COX-2抑制劑有可能增加心血管病發(fā)病危險(xiǎn)，現(xiàn)綜述COX-2抑制劑導(dǎo)致心臟疾病的作用機(jī)制以及目前COX-2抑制劑臨床應(yīng)用進(jìn)展。

引用本文： 王晨,費(fèi)小凡,饒凡,蘇蘭,徐萍蓉. 環(huán)氧化酶-2抑制劑致心血管系統(tǒng)疾病的作用機(jī)制. 華西醫(yī)學(xué), 2011, 26(10): 1581-1584. doi: 復(fù)制

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1. 　Bresalier RS, Sandier RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial[J]. N Engl J Med, 2005, 352(11): 1092-1102.
2. 　Solomon SD, McMurray JV, Pfefer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention [J]. N Engl J Med, 2005, 352(11): 1071-1080.
3. 　李芹, 王睿. 高選擇性COX-2抑制劑羅非昔布撤市分析[J]. 中國(guó)臨床藥理學(xué)與治療學(xué), 2005, 10(3): 259-264.
4. 　Castro MR, Edelman JL, et al. Effect of COX inhibitor on VEGF2 induced retinal vascular leakage and experimental corneal and choroidal neovascularization[J]. Exp Eye Res, 2004, 79(2): 275-285.
5. 　肖偉忠. 環(huán)氧化酶-2與血管形成的關(guān)系[J]. 中國(guó)綜合臨床, 2003, 11(19): 961-962.
6. 　Buerkle MA, Lehrer S, Sohn HY, et al. Selective Inhibition of cyclooxygenase-2 enhances platelet adhesion in hamster arterioles in vivo [J]. Circulation, 2004, 110 (14): 2053-2059.
7. 　Aw TJ, Haas SJ, Liew D, et al. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure [J]. Arch Intern Med, 2005, 165 (5): 490-496.
8. 　Sowers JR, White WB, Pitt B, et al. The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus [J]. Arch Intern Med, 2005, 165 (2): 161-168.
9. 　Dowd NP, Scully M, Adderley SR, et al. Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo[J ]. J Clin Invest, 2001, 108(4): 585-590.
10. 　Delgado RM, Nawar MA, Zewail AM, et al. Cyclooxygenase-2 inhibit or treatment improves left ventricular function and mortality in a murine model of doxorubicin-induced heart failure [J]. Circulation, 2004, 109 (11): 1428-1433.
11. 　LaPointe MC, Mendez M, Leung A, et al. Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse[J]. Am J Physiol Heart Circ Physiol, 2004, 286 (4): 1416-1424.
12. 　Saito T, Rodger IW, Hu F, et al. Inhibition of cyclooxygenase-2 improves cardiac function in myocardial infarction[J]. Biochem Biophys Res Commun, 2000, 273(2): 772-775.
13. 　Brinker A, Goldkind L, Bonnel R, et al. Spontaneous reports of hypertension leading to hospitalisation in association with rofecoxib,celecoxib, nabumetone and oxaprozin[J]. Drugs Aging, 2004, 21(7): 479-484.
14. 　Izhar M, Alausa T, Folker A, et al. Effects of COX inhibition on blood pressure and kidney function in ACE inhibitor-treated blacks and Hispanics[J]. Hypertension, 2004, 43(3): 573-577.
15. 　Blais V, Turrin NP, Rivest S. Cyclooxygenase 2 (COX‐2) inhibition increases the inflammatory response in the brain during systemic immune stimuli[J]. J Neurochem, 2005, 95(6): 1563-1574.
16. 　Zhang F, Warskulat U, Wettste M, et al. Hyperosmolarity stimulates prostaglandin synthesis and cyclooxygenase-2 expression in activated rat liver macrophages[J]. Biochem J, 1995, 312(Pt1): 135-143.
17. 　Smith WL, De Witt DL. Biochemistry of prostaglandin endoperoxide H synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal anti-inflammatory drugs[J]. Semin Nephrol, 1995, 15(3): 179-194.
18. 　Song YG, Kwon HM, Kim JM, et al. Serologic and histopathologic study of Chlamydia pneumoniae infection in atherosclerosis: a possible pathogenetic mechanism of atherosclerosis induced by Chlamydia pneumoniae[J]. Yonsei Med J, 2000, 41(3): 319-327.
19. 　Song W, Furman BL, Parratt JR. Delayed protection against ischemia-induced ventricular arrhythmias and infarct size limitation by the prior administration of Escherichia coli endotoxin[J]. Br J Pharmacol, 1996, 118 (8): 2157-2163.
20. 　Feng L, Xia Y, Garcia GE, et al. Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-alpha and lipopolysaccharide[J]. Clin Invest, 1995, 95(4): 1669-1675.
21. 　Ikonomidis I, Andreotti F, Economou E, et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin [J]. Circulation, 1999, 100(8): 793-798.
22. 　Chenevard R, Hürlimann D, Béchir M, et al. Selective COX-2 inhibition improves endothelial function in coronary artery disease[J]. Circulation, 2003, 107(3): 405-409.
23. 　Wang K, Tarakji KM, Zhou Z, et al. Celecoxib a selective cyclooxygenase-2 inhibitor, decreased monocyte chemoattractant protein-1 expression and neointimal hyperplasia in the rabbit atherosclerotic balloon injury model[J]. J Cardiovas Pharm, 2005, 45(1): 61-67.
24. 　Hawkey CJ. COX-2 inhibitors[J]. Lancet, 1999, 353(9149): 307-314.
25. 　Uefuji K, Ichikura T, Mochizuki H. Cyclooxygenase-2 expression related to prostaglandin biosynthesis and angiogenesis in human gastric cancer [J]. Clin Cancer Res, 2000, 6(1): 135-138.
26. 　孫敬華. 環(huán)氧化酶抑制劑抗腫瘤作用的研究進(jìn)展[J]. 中國(guó)矯形外科雜志, 2005, 13(19): 1505-1507.
27. 　王奇, 鞠名達(dá), 張威廉. 體外循環(huán)心臟手術(shù)對(duì)機(jī)體免疫功能的影響[J]. 中華胸心血管外科雜志, 1995, 11(6): 326-328.
28. 　Gopez JJ, Yue HF, Vasudevan R, et al. Cyclooxygenase-2-specific inhibitor improves functional outcomes provides neuroprotection and reduces inflammation in a rat model of traumatic brain injury[J]. Neurosurgery, 2005, 56(3): 590-604.
29. 　Iadecola C, Gorelick PB. The janus face of cycloxygenase-2 in ischemic stroke: shifting toward downstream targets[J]. Stroke, 2005, 36(2): 182-185.
30. 　Mosheimer BA, Kaneider NC, Feistritzer C. CD4 0ligand-dependent induction of cox-2 gene expression in endothelial cells by activated platelets inhibitory effects of atorvastatin[J]. Blood Coagu Fibri, 2005, 16(2): 105-110.
31. 　Whelton A, John G, Joseph A, et al. cyclooxygenase-2-specific inhibitors and cardiorenal function: a randomized controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients[J]. Am J Ther, 2001, 8(2): 85-95.
32. 　蔣鴻鑫. 環(huán)氧酶-2抑制劑進(jìn)一步松弛逼尿肌導(dǎo)致尿潴留[N]. 中國(guó)醫(yī)學(xué)論壇報(bào), 2002-11-7(6).
33. 　施文, 王永銘, 程能能, 等. 非甾體類抗炎藥的不良反應(yīng)研究進(jìn)展[J]. 中國(guó)臨床藥理雜志, 2003, 19(1): 57-62.
  1. 1. 　Bresalier RS, Sandier RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial[J]. N Engl J Med, 2005, 352(11): 1092-1102.
  2. 2. 　Solomon SD, McMurray JV, Pfefer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention [J]. N Engl J Med, 2005, 352(11): 1071-1080.
  3. 3. 　李芹, 王睿. 高選擇性COX-2抑制劑羅非昔布撤市分析[J]. 中國(guó)臨床藥理學(xué)與治療學(xué), 2005, 10(3): 259-264.
  4. 4. 　Castro MR, Edelman JL, et al. Effect of COX inhibitor on VEGF2 induced retinal vascular leakage and experimental corneal and choroidal neovascularization[J]. Exp Eye Res, 2004, 79(2): 275-285.
  5. 5. 　肖偉忠. 環(huán)氧化酶-2與血管形成的關(guān)系[J]. 中國(guó)綜合臨床, 2003, 11(19): 961-962.
  6. 6. 　Buerkle MA, Lehrer S, Sohn HY, et al. Selective Inhibition of cyclooxygenase-2 enhances platelet adhesion in hamster arterioles in vivo [J]. Circulation, 2004, 110 (14): 2053-2059.
  7. 7. 　Aw TJ, Haas SJ, Liew D, et al. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure [J]. Arch Intern Med, 2005, 165 (5): 490-496.
  8. 8. 　Sowers JR, White WB, Pitt B, et al. The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus [J]. Arch Intern Med, 2005, 165 (2): 161-168.
  9. 9. 　Dowd NP, Scully M, Adderley SR, et al. Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo[J ]. J Clin Invest, 2001, 108(4): 585-590.
  10. 10. 　Delgado RM, Nawar MA, Zewail AM, et al. Cyclooxygenase-2 inhibit or treatment improves left ventricular function and mortality in a murine model of doxorubicin-induced heart failure [J]. Circulation, 2004, 109 (11): 1428-1433.
  11. 11. 　LaPointe MC, Mendez M, Leung A, et al. Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse[J]. Am J Physiol Heart Circ Physiol, 2004, 286 (4): 1416-1424.
  12. 12. 　Saito T, Rodger IW, Hu F, et al. Inhibition of cyclooxygenase-2 improves cardiac function in myocardial infarction[J]. Biochem Biophys Res Commun, 2000, 273(2): 772-775.
  13. 13. 　Brinker A, Goldkind L, Bonnel R, et al. Spontaneous reports of hypertension leading to hospitalisation in association with rofecoxib,celecoxib, nabumetone and oxaprozin[J]. Drugs Aging, 2004, 21(7): 479-484.
  14. 14. 　Izhar M, Alausa T, Folker A, et al. Effects of COX inhibition on blood pressure and kidney function in ACE inhibitor-treated blacks and Hispanics[J]. Hypertension, 2004, 43(3): 573-577.
  15. 15. 　Blais V, Turrin NP, Rivest S. Cyclooxygenase 2 (COX‐2) inhibition increases the inflammatory response in the brain during systemic immune stimuli[J]. J Neurochem, 2005, 95(6): 1563-1574.
  16. 16. 　Zhang F, Warskulat U, Wettste M, et al. Hyperosmolarity stimulates prostaglandin synthesis and cyclooxygenase-2 expression in activated rat liver macrophages[J]. Biochem J, 1995, 312(Pt1): 135-143.
  17. 17. 　Smith WL, De Witt DL. Biochemistry of prostaglandin endoperoxide H synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal anti-inflammatory drugs[J]. Semin Nephrol, 1995, 15(3): 179-194.
  18. 18. 　Song YG, Kwon HM, Kim JM, et al. Serologic and histopathologic study of Chlamydia pneumoniae infection in atherosclerosis: a possible pathogenetic mechanism of atherosclerosis induced by Chlamydia pneumoniae[J]. Yonsei Med J, 2000, 41(3): 319-327.
  19. 19. 　Song W, Furman BL, Parratt JR. Delayed protection against ischemia-induced ventricular arrhythmias and infarct size limitation by the prior administration of Escherichia coli endotoxin[J]. Br J Pharmacol, 1996, 118 (8): 2157-2163.
  20. 20. 　Feng L, Xia Y, Garcia GE, et al. Involvement of reactive oxygen intermediates in cyclooxygenase-2 expression induced by interleukin-1, tumor necrosis factor-alpha and lipopolysaccharide[J]. Clin Invest, 1995, 95(4): 1669-1675.
  21. 21. 　Ikonomidis I, Andreotti F, Economou E, et al. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin [J]. Circulation, 1999, 100(8): 793-798.
  22. 22. 　Chenevard R, Hürlimann D, Béchir M, et al. Selective COX-2 inhibition improves endothelial function in coronary artery disease[J]. Circulation, 2003, 107(3): 405-409.
  23. 23. 　Wang K, Tarakji KM, Zhou Z, et al. Celecoxib a selective cyclooxygenase-2 inhibitor, decreased monocyte chemoattractant protein-1 expression and neointimal hyperplasia in the rabbit atherosclerotic balloon injury model[J]. J Cardiovas Pharm, 2005, 45(1): 61-67.
  24. 24. 　Hawkey CJ. COX-2 inhibitors[J]. Lancet, 1999, 353(9149): 307-314.
  25. 25. 　Uefuji K, Ichikura T, Mochizuki H. Cyclooxygenase-2 expression related to prostaglandin biosynthesis and angiogenesis in human gastric cancer [J]. Clin Cancer Res, 2000, 6(1): 135-138.
  26. 26. 　孫敬華. 環(huán)氧化酶抑制劑抗腫瘤作用的研究進(jìn)展[J]. 中國(guó)矯形外科雜志, 2005, 13(19): 1505-1507.
  27. 27. 　王奇, 鞠名達(dá), 張威廉. 體外循環(huán)心臟手術(shù)對(duì)機(jī)體免疫功能的影響[J]. 中華胸心血管外科雜志, 1995, 11(6): 326-328.
  28. 28. 　Gopez JJ, Yue HF, Vasudevan R, et al. Cyclooxygenase-2-specific inhibitor improves functional outcomes provides neuroprotection and reduces inflammation in a rat model of traumatic brain injury[J]. Neurosurgery, 2005, 56(3): 590-604.
  29. 29. 　Iadecola C, Gorelick PB. The janus face of cycloxygenase-2 in ischemic stroke: shifting toward downstream targets[J]. Stroke, 2005, 36(2): 182-185.
  30. 30. 　Mosheimer BA, Kaneider NC, Feistritzer C. CD4 0ligand-dependent induction of cox-2 gene expression in endothelial cells by activated platelets inhibitory effects of atorvastatin[J]. Blood Coagu Fibri, 2005, 16(2): 105-110.
  31. 31. 　Whelton A, John G, Joseph A, et al. cyclooxygenase-2-specific inhibitors and cardiorenal function: a randomized controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients[J]. Am J Ther, 2001, 8(2): 85-95.
  32. 32. 　蔣鴻鑫. 環(huán)氧酶-2抑制劑進(jìn)一步松弛逼尿肌導(dǎo)致尿潴留[N]. 中國(guó)醫(yī)學(xué)論壇報(bào), 2002-11-7(6).
  33. 33. 　施文, 王永銘, 程能能, 等. 非甾體類抗炎藥的不良反應(yīng)研究進(jìn)展[J]. 中國(guó)臨床藥理雜志, 2003, 19(1): 57-62.