title: Microsomal Prostaglandin E Synthase-1-Derived PGE2 Inhibits Vascular Smooth Muscle Cell Calcification.
abstract: OBJECTIVE
  Chronic administration of selective cyclooxygenase-2 (COX-2) inhibitors leads to an increased risk of adverse cardiovascular events, including myocardial infarction and stroke. Vascular smooth muscle cell (VSMC) calcification, a common complication of chronic kidney disease, is directly related to cardiovascular morbidity and mortality. Here, we tested whether specific COX-2 inhibition affects vascular calcification during chronic renal failure.
  
  
  RESULTS
  The COX-2-specific inhibitors NS398 and SC236 significantly increased high-phosphate (Pi)-induced VSMC calcification. Similarly, COX-2(-/-) VSMCs, COX-2(-/-) aortas rings treated with high Pi and adenine diet-induced COX-2(-/-) chronic renal failure mice displayed enhanced calcium deposition. Metabolomic analysis revealed the differential suppression of PGE2 production by COX-1- and COX-2-specific inhibitors in high-Pi-stimulated VSMCs, indicating the involvement of PGE2 during COX-2 inhibition-aggravated vascular calcification. Indeed, exogenous PGE2 reduced alkaline phosphatase activity, osteogenic transdifferentiation, apoptosis, and calcification of VSMCs. In accordance, downregulation of microsomal prostaglandin E synthase (mPGES)-1 in VSMCs, mPGES-1(-/-) aorta with high-Pi stimulation and mPGES-1(-/-) chronic renal failure mice resulted in enhanced vascular mineralization. Further applications of RNAi and specific antagonists for PGE2 receptors indicated EP4 may mediate PGE2-inhibited vascular calcification.
  
  
  CONCLUSIONS
  Our data revealed the pivotal role of COX-2-mPGES-1-PGE2 axis in vascular calcification. The selective inhibition of COX-2 or mPGES-1 may increase the risk of calcification and subsequent adverse cardiovascular events during chronic renal failure.
authors.affiliation: From the Department of Physiology and Pathophysiology (C.G., Y.F., X.Z., L.Z., F.Y., Y.Z., Y.G., X.W., W.K.) and Institute of Cardiovascular Sciences (Y.L.), School of Basic Medical Sciences, Peking University, Beijing, P.R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P.R. China (C.G., Y.F., Y.L., X.Z., L.Z., F.Y., Y.Z., Y.G., X.W., W.K.); Gonville and Caius College, University of Cambridge, Cambridge, United Kingdom (S.S.X.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Cheng
authors.initials: C
authors.lastname: Gao
authors.affiliation: From the Department of Physiology and Pathophysiology (C.G., Y.F., X.Z., L.Z., F.Y., Y.Z., Y.G., X.W., W.K.) and Institute of Cardiovascular Sciences (Y.L.), School of Basic Medical Sciences, Peking University, Beijing, P.R. China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, P.R. China (C.G., Y.F., Y.L., X.Z., L.Z., F.Y., Y.Z., Y.G., X.W., W.K.); Gonville and Caius College, University of Cambridge, Cambridge, United Kingdom (S.S.X.); and Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Q.X.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Fu
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.forename: Susanna S
authors.initials: SS
authors.lastname: Xu
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
mesh_terms: D000225:Adenine; D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology / Q000473:pathology; D001013:Aorta, Thoracic / Q000201:enzymology / Q000473:pathology; D001018:Aortic Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D002117:Calcitriol; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000633:toxicity; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D008297:Male; D055432:Metabolomics / Q000379:methods; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009392:Nephrectomy; D010710:Phosphates; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D061205:Vascular Calcification / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D010710:Phosphates; C545652:Ptger4 protein, rat; D058309:Receptors, Prostaglandin E, EP4 Subtype; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C489691:Ptgs2 protein, rat; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; C497818:Ptges protein, rat; D002117:Calcitriol; D000225:Adenine; D015232:Dinoprostone
keywords: adenine; calcium; myocardial infarction; phosphates; vascular calcification