Abstract 12756: Cardioprotection by Heme Oxygenase-1 is Mediated by Cyclooxygenase-2 but not Inducible Nitric Oxide Synthase
Although heme oxygenase-1 (HO-1) is known to exert powerful cardioprotective actions, the mechanism remains unclear. HO-1 mediates the beneficial effects of the late phase of preconditioning along with inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2); however, the interrelations among these proteins are uncertain. In particular, little is known regarding the relationship between HO-1 and COX-2. To gain insights into this issue, wildtype littermate and cardiac specific HO-1 transgenic (Tg) mice were subjected to a 30-min coronary artery occlusion followed by 24 h of reperfusion. Compared with control mice (WT, group I), infarct size was markedly reduced in HO-1 Tg mice (group II) (54.2 ± 3.7% vs. 33.0 ± 5.8% of the risk region), documenting the cardioprotective effect of HO-1 (Figure). As expected, HO-1-induced protection was eliminated when mice were given the HO-1 inhibitor SnPP9 (150 mg/kg, ip) 4 hours before coronary artery occlusion (group IV) (50.5 ± 3.8% vs. 56.0 ± 3.4% of the risk region, respectively). Pretreatment of mice with the iNOS inhibitor 1400W (group VI, 20 mg/kg, ip) had no effect on HO-1-dependent protection (45.8 ± 5.6% vs. 23.9 ± 3.4% of the risk region) (Figure). In contrast, pretreatment of mice with the COX-2 inhibitor NS-398 (group VIII, 5 mg/kg, ip) completely abrogated HO-1-induced protection (58.1 ± 4.1% vs. 61.6 ± 5.1% of the risk region). Thus, the cardioprotective actions of HO-1 are independent of iNOS but require COX-2 activity. The finding that COX-2 is a necessary mediator of HO-1-dependent protection is novel, and reveals a new mechanism of action of this multifarious cytoprotective protein.
- © 2010 by American Heart Association, Inc.