title: Constitutive COX-2 activity in cardiomyocytes confers permanent cardioprotection Constitutive COX-2 expression and cardioprotection.
abstract: Different lines of evidence suggest that inhibition of COX-2 activity exacerbates reperfusion injury, but direct data showing beneficial effects of increased COX-2 activity are lacking. The aim of this study was to determine the effect of constitutive expression of COX-2 on cardiomyocyte tolerance to ischemia-reperfusion injury. We generated a transgenic mouse (B6D2-Tg (MHC-PTGS2)17Upme) that constitutively expresses functional human COX-2 in cardiomyocytes under the control of alpha-myosin heavy chain promoter. COX-2 expression was confirmed by immunoblotting and by increased levels of PGE(2) and PGI(2) in myocardium. Histological and echocardiographic analysis revealed no differences in the phenotype of transgenic mice (TgCOX-2) with respect to wild type (Wt) mice. Tolerance to ischemia-reperfusion injury was analysed in a Langendorff system. Reperfused TgCOX-2 hearts after 40 min of ischemia improved functional recovery (32.9+/-6.2% vs. 9.45+/-4.4%, P=0.004) and reduced cell death assessed by LDH release (43% of reduction, P<0.001) and triphenyltetrazolium staining (41% of reduction, P=0.002). Cardioprotection was not further increased by ischemic preconditioning. Pretreatment of mice with the COX-2 inhibitor DFU attenuated cardioprotection with a correlation between myocardial PGE(2) levels and the extent of cell death. NMR spectroscopy showed a marked reduction in arachidonic acid (AA) content in TgCOX-2 hearts. Both, DFU pretreatment and perfusion of TgCOX-2 hearts with AA increased myocardial AA to values similar to those measured in Wt hearts and reversed cardioprotection. We conclude that constitutive expression of COX-2 in cardiomyocytes confers a permanent cardioprotective state against reperfusion injury. Increased PGE(2) synthesis and reduced AA content could explain this effect.
authors.affiliation: Servicio de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Inserte
authors.forename: Belén
authors.initials: B
authors.lastname: Molla
authors.forename: Rio
authors.initials: R
authors.lastname: Aguilar
authors.forename: Paqui G
authors.initials: PG
authors.lastname: Través
authors.forename: Ignasi
authors.initials: I
authors.lastname: Barba
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.forename: Marta
authors.initials: M
authors.lastname: Casado
authors.forename: David
authors.initials: D
authors.lastname: Garcia-Dorado
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology*; D004452:Echocardiography; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism*
chemical_list: D016718:Arachidonic Acid; D051546:Cyclooxygenase 2