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: Javier Inserte, Belén Molla, Rio Aguilar, Paqui G Través, Ignasi Barba, Paloma Martín-Sanz, Lisardo Boscá, Marta Casado, David Garcia-Dorado
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 46 Issue 2 Pg. 160-8 (Feb 2009) ISSN: 1095-8584 [Electronic] England
• PMID: 19084534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arachidonic Acid
• Cyclooxygenase 2

Topics

• Animals
• Arachidonic Acid (metabolism)
• Cyclooxygenase 2 (genetics, physiology)
• Echocardiography
• Female
• Fluorescent Antibody Technique
• Humans
• Magnetic Resonance Spectroscopy
• Male
• Mice
• Mice, Transgenic
• Myocardial Reperfusion Injury (genetics, prevention & control)
• Myocytes, Cardiac (metabolism)