title: Lack of microsomal prostaglandin E(2) synthase-1 in bone marrow-derived myeloid cells impairs left ventricular function and increases mortality after acute myocardial infarction.
abstract: BACKGROUND
  Microsomal prostaglandin E(2) synthase-1 (mPGES-1), encoded by the Ptges gene, catalyzes prostaglandin E(2) biosynthesis and is expressed by leukocytes, cardiac myocytes, and cardiac fibroblasts. Ptges(-/-) mice develop more left ventricle (LV) dilation, worse LV contractile function, and higher LV end-diastolic pressure than Ptges(+/+) mice after myocardial infarction. In this study, we define the role of mPGES-1 in bone marrow-derived leukocytes in the recovery of LV function after coronary ligation.
  
  
  RESULTS
  Cardiac structure and function in Ptges(+/+) mice with Ptges(+/+) bone marrow (BM(+/+)) and Ptges(+/+) mice with Ptges(-/-) BM (BM(-/-)) were assessed by morphometric analysis, echocardiography, and invasive hemodynamics before and 7 and 28 days after myocardial infarction. Prostaglandin levels and prostaglandin biosynthetic enzyme gene expression were measured by liquid chromatography-tandem mass spectrometry and real-time polymerase chain reaction, immunoblotting, immunohistochemistry, and immunofluorescence microscopy, respectively. After myocardial infarction, BM(-/-) mice had more LV dilation, worse LV systolic and diastolic function, higher LV end-diastolic pressure, more cardiomyocyte hypertrophy, and higher mortality but similar infarct size and pulmonary edema compared with BM(+/+) mice. BM(-/-) mice also had higher levels of COX-1 protein and more leukocytes in the infarct, but not the viable LV, than BM(+/+) mice. Levels of prostaglandin E(2) were higher in the infarct and viable myocardium of BM(-/-) mice than in BM(+/+) mice.
  
  
  CONCLUSIONS
  Lack of mPGES-1 in bone marrow-derived leukocytes negatively regulates COX-1 expression, prostaglandin E(2) biosynthesis, and inflammation in the infarct and leads to impaired LV function, adverse LV remodeling, and decreased survival after acute myocardial infarction.
authors.affiliation: Division of Vascular Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Norbert
authors.initials: N
authors.lastname: Degousee
authors.forename: Jeremy
authors.initials: J
authors.lastname: Simpson
authors.forename: Shafie
authors.initials: S
authors.lastname: Fazel
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
authors.forename: Denis
authors.initials: D
authors.lastname: Angoulvant
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Marina
authors.initials: M
authors.lastname: Korotkova
authors.forename: Eva
authors.initials: E
authors.lastname: Stefanski
authors.forename: Xing-Hua
authors.initials: XH
authors.lastname: Wang
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lindsay
authors.forename: Efrat
authors.initials: E
authors.lastname: Ofek
authors.forename: Sandra
authors.initials: S
authors.lastname: Pierre
authors.forename: Jagdish
authors.initials: J
authors.lastname: Butany
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.forename: Armand
authors.initials: A
authors.lastname: Keating
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.forename: Barry B
authors.initials: BB
authors.lastname: Rubin
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001854:Bone Marrow Cells / Q000201:enzymology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003971:Diastole / Q000502:physiology; D004195:Disease Models, Animal; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000201:enzymology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology*; D022423:Myeloid Cells / Q000201:enzymology*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D009205:Myocarditis / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D000071876:Prostaglandin-E Synthases; D013599:Systole / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D008565:Membrane Proteins; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse