Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI2: a safer alternative to COX-2 inhibition

被引：47

作者：

Ozen, Gulsev ^{[1
,2
]}

Gomez, Ingrid ^{[1
,3
]}

Daci, Armond ^{[2
]}

Deschildre, Catherine ^{[1
]}

Boubaya, Lilia ^{[1
]}

Teskin, Onder ^{[4
]}

Uydes-Dogan, B. Sonmez ^{[2
]}

Jakobsson, Per-Johan ^{[5
,6
]}

Longrois, Dan ^{[1
,7
]}

Topal, Gokce

Norel, Xavier ^{[1
,8
]}

机构：

[1] INSERM, U1148, Paris, France

[2] Istanbul Univ, Dept Pharmacol, Fac Pharm, Istanbul, Turkey

[3] Univ Sheffield, Sch Med & Biomed Sci, Dept Infect Immun & Cardiovasc Dis, Sheffield, S Yorkshire, England

[4] Aile Hosp, Dept Cardiovasc Surg, Istanbul, Turkey

[5] Karolinska Inst, Dept Med Solna, Unit Rheumatol, Stockholm, Sweden

[6] Karolinska Univ Hosp, Unit Rheumatol, Stockholm, Sweden

[7] Univ Paris Diderot, CHU X Bichat, AP HP, Sorbonne Paris Cite,UMR S1148,Dept Anesthesia & I, Paris, France

[8] Univ Paris Diderot, Sorbonne Paris Cite, UMR S1148, Paris, France

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2017年 / 174卷 / 22期

关键词：

PROSTAGLANDIN-E SYNTHASE-1; MAMMARY ARTERY; CONCISE GUIDE; CARDIOVASCULAR BIOLOGY; SAPHENOUS-VEIN; SMOOTH-MUSCLE; NITRIC-OXIDE; CYCLOOXYGENASE-2; PHARMACOLOGY; E-2;

D O I：

10.1111/bph.13939

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

BACKGROUND AND PURPOSE The side effects of cyclooxygenase-2 (COX-2) inhibitors on the cardiovascular system could be associated with reduced prostaglandin (PG)I-2 synthesis. Microsomal PGE synthase-1 (mPGES-1) catalyses the formation of PGE(2) from COX-derived PGH(2). This enzyme is induced under inflammatory conditions and constitutes an attractive target for novel anti-inflammatory drugs. However, it is not known whether mPGES-1 inhibitors could be devoid of cardiovascular side effects. The aim of this study was to compare, in vitro, the effects of mPGES-1 and COX-2 inhibitors on vascular tone in human blood vessels. EXPERIMENTAL APPROACH The vascular tone and prostanoid release from internalmammary artery (IMA) and saphenous vein (SV) incubated for 30 min with inhibitors of mPGES-1 or COX-2 were investigated under normal and inflammatory conditions. KEY RESULTS In inflammatory conditions, mPGES-1 and COX-2 proteins were more expressed, and increased levels of PGE(2) and PGI(2) were released. COX-2 and NOS inhibitors increased noradrenaline induced vascular contractions in IMA under inflammatory conditions while no effect was observed in SV. Interestingly, the mPGES-1 inhibitor significantly reduced (30-40%) noradrenaline-induced contractions in both vessels. This effect was reversed by an IP (PGI(2) receptor) antagonist but not modified by NOS inhibition. Moreover, PGI(2) release was increased with the mPGES-1 inhibitor and decreased with the COX-2 inhibitor, while both inhibitors reduced PGE(2) release. CONCLUSIONS AND IMPLICATIONS In contrast to COX-2 inhibition, inhibition ofmPGES-1 reduced vasoconstriction by increasing PGI(2) synthesis. Targetingm-PGES-1 could provide a lower risk of cardiovascular side effects, compared with those of the COX-2 inhibitors.

引用

页码：4087 / 4098

页数：12

共 44 条

[1] Evidence That Links Loss of Cyclooxygenase-2 With Increased Asymmetric Dimethylarginine Novel Explanation of Cardiovascular Side Effects Associated With Anti-Inflammatory Drugs [J].

Ahmetaj-Shala, Blerina ;

Kirkby, Nicholas S. ;

Knowles, Rebecca ;

Al'Yamani, Malak ;

Mazi, Sarah ;

Wang, Zhen ;

Tucker, Arthur T. ;

Mackenzie, Louise ;

Armstrong, Paul C. J. ;

Nuesing, Rolf M. ;

Tomlinson, James A. P. ;

Warner, Timothy D. ;

Leiper, James ;

Mitchell, Jane A. .

CIRCULATION, 2015, 131 (07) :633-U113

[2] THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors [J].

Alexander, Stephen P. H. ;

Davenport, Anthony P. ;

Kelly, Eamonn ;

Marrion, Neil ;

Peters, John A. ;

Benson, Helen E. ;

Faccenda, Elena ;

Pawson, Adam J. ;

Sharman, Joanna L. ;

Southan, Christopher ;

Davies, Jamie A. ;

Aldrich, R. ;

Attali, B. ;

Back, M. ;

Barnes, N. M. ;

Bathgate, R. ;

Beart, P. M. ;

Becirovic, E. ;

Biel, M. ;

Birdsall, N. J. ;

Boison, D. ;

Brauner-Osborne, H. ;

Broeer, S. ;

Bryant, C. ;

Burnstock, G. ;

Burris, T. ;

Cain, D. ;

Calo, G. ;

Chan, S. L. ;

Chandy, K. G. ;

Chiang, N. ;

Christakos, S. ;

Christopoulos, A. ;

Chun, J. J. ;

Chung, J. -J. ;

Clapham, D. E. ;

Connor, M. A. ;

Coons, L. ;

Cox, H. M. ;

Dautzenberg, F. M. ;

Dent, G. ;

Douglas, S. D. ;

Dubocovich, M. L. ;

Edwards, D. P. ;

Farndale, R. ;

Fong, T. M. ;

Forrest, D. ;

Fowler, C. J. ;

Fuller, P. ;

Gainetdinov, R. R. .

BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (24) :5744-5869

[3] THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Enzymes [J].

Alexander, Stephen P. H. ;

Fabbro, Doriano ;

Kelly, Eamonn ;

Marrion, Neil ;

Peters, John A. ;

Benson, Helen E. ;

Faccenda, Elena ;

Pawson, Adam J. ;

Sharman, Joanna L. ;

Southan, Christopher ;

Davies, Jamie A. ;

Aldrich, R. ;

Attali, B. ;

Back, M. ;

Barnes, N. M. ;

Bathgate, R. ;

Beart, P. M. ;

Becirovic, E. ;

Biel, M. ;

Birdsall, N. J. ;

Boison, D. ;

Brauner-Osborne, H. ;

Broeer, S. ;

Bryant, C. ;

Burnstock, G. ;

Burris, T. ;

Cain, D. ;

Calo, G. ;

Chan, S. L. ;

Chandy, K. G. ;

Chiang, N. ;

Christakos, S. ;

Christopoulos, A. ;

Chun, J. J. ;

Chung, J. -J. ;

Clapham, D. E. ;

Connor, M. A. ;

Coons, L. ;

Cox, H. M. ;

Dautzenberg, F. M. ;

Dent, G. ;

Douglas, S. D. ;

Dubocovich, M. L. ;

Edwards, D. P. ;

Farndale, R. ;

Fong, T. M. ;

Forrest, D. ;

Fowler, C. J. ;

Fuller, P. ;

Gainetdinov, R. R. .

BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (24) :6024-6109

[4] THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Catalytic receptors [J].

Alexander, Stephen P. H. ;

Fabbro, Doriano ;

Kelly, Eamonn ;

Marrion, Neil ;

Peters, John A. ;

Benson, Helen E. ;

Faccenda, Elena ;

Pawson, Adam J. ;

Sharman, Joanna L. ;

Southan, Christopher ;

Davies, Jamie A. ;

Aldrich, R. ;

Attali, B. ;

Back, M. ;

Barnes, N. M. ;

Bathgate, R. ;

Beart, P. M. ;

Becirovic, E. ;

Biel, M. ;

Birdsall, N. J. ;

Boison, D. ;

Brauner-Osborne, H. ;

Broeer, S. ;

Bryant, C. ;

Burnstock, G. ;

Burris, T. ;

Cain, D. ;

Calo, G. ;

Chan, S. L. ;

Chandy, K. G. ;

Chiang, N. ;

Christakos, S. ;

Christopoulos, A. ;

Chun, J. J. ;

Chung, J. -J. ;

Clapham, D. E. ;

Connor, M. A. ;

Coons, L. ;

Cox, H. M. ;

Dautzenberg, F. M. ;

Dent, G. ;

Douglas, S. D. ;

Dubocovich, M. L. ;

Edwards, D. P. ;

Farndale, R. ;

Fong, T. M. ;

Forrest, D. ;

Fowler, C. J. ;

Fuller, P. ;

Gainetdinov, R. R. .

BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (24) :5979-6023

[5] Long-term NSAID treatment directly decreases COX-2 and mPGES-1 production in the articular cartilage of patients with osteoarthritis [J].

Alvarez-Soria, M. A. ;

Herrero-Beaumont, G. ;

Moreno-Rubio, J. ;

Calvo, E. ;

Santillana, J. ;

Egido, J. ;

Largo, R. .

OSTEOARTHRITIS AND CARTILAGE, 2008, 16 (12) :1484-1493

[6] Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials [J].

Bhala, N. ;

Emberson, J. ;

Merhi, A. ;

Abramson, S. ;

Arber, N. ;

Baron, J. A. ;

Bombardier, C. ;

Cannon, C. ;

Farkouh, M. E. ;

FitzGerald, G. A. ;

Goss, P. ;

Halls, H. ;

Hawk, E. ;

Hawkey, C. ;

Hennekens, C. ;

Hochberg, M. ;

Holland, L. E. ;

Kearney, P. M. ;

Laine, L. ;

Lanas, A. ;

Lance, P. ;

Laupacis, A. ;

Oates, J. ;

Patrono, C. ;

Schnitzer, T. J. ;

Solomon, S. ;

Tugwell, P. ;

Wilson, K. ;

Wittes, J. ;

Baigent, C. ;

Adelowo, O. ;

Aisen, P. ;

Al-Quorain, A. ;

Altman, R. ;

Bakris, G. ;

Baumgartner, H. ;

Bresee, C. ;

Carducci, M. ;

Chang, D-M. ;

Chou, C-T. ;

Clegg, D. ;

Cudkowicz, M. ;

Doody, L. ;

El Miedany, Y. ;

Falandry, C. ;

Farley, J. ;

Ford, L. ;

GarciLosa, M. ;

Gonzalez-Ortiz, M. ;

Haghighi, M. .

LANCET, 2013, 382 (9894) :769-779

[7] Differential induction of cyclooxygenase-2 in human arterial and venous smooth muscle - Role of endogenous prostanoids [J].

Bishop-Bailey, D ;

Pepper, JR ;

Larkin, SW ;

Mitchell, JA .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1998, 18 (10) :1655-1661

[8] Microsomal prostaglandin E synthase-1, which is not coupled to a particular cyclooxygenase isoenzyme, is essential for prostaglandin E2 biosynthesis in vascular smooth muscle cells [J].

Camacho, M. ;

Gerboles, E. ;

Escudero, J.-R. ;

Anton, R. ;

Garcia-Moll, X. ;

Vila, L. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2007, 5 (07) :1411-1419

[9] Identification and Characterization of Novel Microsomal Prostaglandin E Synthase-1 Inhibitors for Analgesia [J].

Chandrasekhar, Srinivasan ;

Harvey, Anita K. ;

Yu, Xiao-Peng ;

Chambers, Mark G. ;

Oskins, Jennifer L. ;

Lin, Chaohua ;

Seng, Thomas W. ;

Thibodeaux, Stefan J. ;

Norman, Bryan H. ;

Hughes, Norman E. ;

Schiffler, Matthew A. ;

Fisher, Matthew J. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2016, 356 (03) :635-644

[10] Cell Selective Cardiovascular Biology of Microsomal Prostaglandin E Synthase-1 [J].

Chen, Lihong ;

Yang, Guangrui ;

Xu, Xiufeng ;

Grant, Gregory ;

Lawson, John A. ;

Bohlooly-Y, Mohammad ;

FitzGerald, Garret A. .

CIRCULATION, 2013, 127 (02) :233-+

← 1 2 3 4 5 →