Abstract 1615: Mice with Inducible Cardiac-Specific Overexpression of Cyclooxygenase-2 Are More Resistant to Ischemia/Reperfusion Injury
The role of cyclooxygenase-2 (COX-2) in cardiovascular biology continues to be controversial. Although COX-2 has been reported to mediate the protective actions of late preconditioning, other studies seem to support a deleterious effect of this enzyme. To elucidate this issue, we determined the effects of inducible cardiac-specific COX-2 overexpression on myocardial infarction (MI). We created cardiac-specific, inducible (Tet-off) COX-2 transgenic mice (iCOX-2 Tg [αMyHC-tTA;TRE/CMV-COX-2]) by breeding αMyHC-tTA transgenic mice (tetracycline transactivator [tTA] under the cardiac-specific α-myosin heavy chain promoter [αMyHC]) with TRE/CMV-COX-2 Tg mice (COX-2 under the control of inducible heterologous TRE-CMV promoter). Three months after COX-2 induction, iCOX-2 Tg (group II, n=13) and iCOX-2 WT (group I, n=11) mice were subjected to a 30-min coronary occlusion and 24 h of reperfusion. In WT mice, infarct size was 52.7±4.6% of the risk region (Figure⇓). When iCOX-2 Tg mice were subjected to the same protocol, however, infarct size was much smaller (22.4±3.3%), indicating that overexpression of the COX-2 gene has a potent cardioprotective effect. We conclude that inducible cardiac-specific overexpression of COX-2 exerts a potent cardioprotective effect against MI in mice, and that this effect persists for sustained periods (at least 3 months). Thus, COX-2 in itself (independent of other proteins upregulated by preconditioning) is cytoprotective. The concept that COX-2 is chronically protective has important therapeutic implications for studies of long-term gene therapy aimed at increasing myocardial COX-2 content as well as for other COX-2-based strategies.