Abstract 368: Identification of Inducible Nitric Oxide Synthase in Peripheral Blood Cells as a Mediator of Myocardial Ischemia/Reperfusion Injury
To test the hypothesis that inducible nitric oxide synthase (iNOS) in inflammatory cells exacerbates myocardial ischemia/reperfusion injury, we created chimeric mice with iNOS deficient peripheral blood by transplanting iNOS KO bone marrow in wild-type (WT) B6129F2 mice after lethal irradiation. Two months later, mice underwent a 30-min coronary occlusion and 24 h of reperfusion. In WT naïve mice (group I), infarct size was 58.6±1.8% of risk region (Fig⇓). In iNOS KO naïve mice with whole-body iNOS deletion (group II), infarct size was not different (53.4±3.5%). When irradiated WT mice received marrow from WT mice (iNOS+/+ chimera, group III), infarct size was slightly reduced vs. group I (44.3±3.2%) indicating that irradiation and/or transplantation alone limit infarct size. However, when WT mice received marrow from iNOS KO mice (iNOS−/− chimera, group IV), infarct size was markedly reduced (22.8±2.1%, P<0.05 vs. irradiation and transplant of WT bone marrow (group III), indicating that selective deletion of iNOS from peripheral blood cells (with no change in myocardial iNOS content) induces protection against MI. Our results identify iNOS in peripheral blood cells as a mediator of myocardial ischemia/reperfusion injury. Together with our previous work showing that iNOS gene transfer to myocardium is protective, these data support a complex, dual role of iNOS in MI, i.e., protective in myocytes but deleterious in blood cells (presumably via formation of NO-derived peroxynitrite. This concept may also have important therapeutic implications, e.g., protection with iNOS gene therapy to increase myocyte iNOS content may be augmented by decreasing blood cell iNOS expression.
This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).