Abstract 551: The Cardioprotection Afforded by Inducible Nitric Oxide Synthase Is Mediated by Heme Oxygenase-1
Although it well established that iNOS protects against infarction, the mechanism of this salubrious action remains unclear. We tested the hypothesis that the cardioprotection afforded by iNOS is mediated by induction of HO-1, a cytoprotective enzyme that plays a critical role in response to various stresses. To achieve selective iNOS upregulation (without other cellular perturbations associated with ischemic preconditioning), we used iNOS gene therapy mediated by an Ad5 vector with deletions of E1, E2a, and E3 regions (Av3). Mice received an intramyocardial injection in the anterior LV wall of Av3/LacZ (LacZ group) or Av3/iNOS (iNOS group); 3 days later, they were subjected to myocardial infarction (30-min coronary occlusion/4 h reperfusion). iNOS gene transfer resulted not only in increased myocardial expression of iNOS but also in increased myocardial HO-1 protein expression (+263% vs. LacZ group, n=6; P<0.05). In contrast, HO-2 protein expression did not change (n=3). Infarct size (% of risk region) was markedly reduced by iNOS gene therapy in wild-type (WT) mice (13.7±4.0%, n=8, vs. 46.6±4.5% in LacZ group, n=9; Fig⇓); this effect was completely abrogated in HO-1 knockout (KO) mice (44.0±4.3%, n=6; Fig⇓). We conclude that
upregulation of iNOS per se, in the absence of ischemia or other stimuli, induces myocardial HO-1 protein expression, and
HO-1 is an obligatory downstream effector of iNOS-dependent cardioprotection.
These data reveal a new mechanism of iNOS-dependent protection in vivo. A sensitive coupling has evolved between iNOS and HO-1, whereby upregulation of iNOS leads to elevated expression of HO-1, which is necessary for iNOS-dependent cardioprotection.