Abstract 13493: Complete Disruption of All Nitric Oxide Synthase Genes Markedly Reduces Cerebral Infarct Size after Middle Cerebral Artery Occlusion in Mice
Background: The role of each nitric oxide synthase (NOS) isoform in the pathogenesis of cerebral infarction has been studied in individual NOS isoform-deficient mice. It has been reported that, in a model of middle cerebral artery occlusion (MCAO), neuronal and inducible NOSs exacerbate cerebral infarction, whereas endothelial NOS conversely alleviates cerebral infarction. Although the role of the whole NOSs system in cerebral infarction has been examined in pharmacological studies with non-selective NOS inhibitors, the results are quit inconsistent, possibly because of non-specificity of the agents. In this study, we addressed this point in mice in which all three NOS genes are completely disrupted.
Method and Results: We newly generated triple NOSs-deficient mice and wild-type littermates by crossbreeding single NOS-/- mice. Transient (1 hour) and permanent MCAO was performed in male triple NOSs-/- and wild-type mice at 8-12 weeks of age (n=9-11). Cerebral infarct size was evaluated by triphenyltetrazolium chloride (TTC) staining. There was no anatomical difference in the structure of cerebral arteries between the triple NOSs-/- and wild-type mice (n=3 each). Reductions in cerebral blood flow during MCAO were identical between the two mice. However, cerebral infarct size at 24 hours after transient MCAO was markedly smaller in the triple NOSs-/- than in the wild-type mice (P<0.05, n=8-12). Cerebral infarct size at 24 hours after permanent MCAO was also markedly decreased in the triple NOSs-/- mice as compared with the wild-type mice (P<0.05, n=8-10). In addition, neurological deficit was significantly less and the survival rate was significantly better in the triple NOSs-/- mice compared with the wild-type mice (both P<0.05, n=8-12).
Conclusions: These results provide the first evidence that complete disruption of all NOS genes markedly reduces cerebral infarct size after MCAO in mice, demonstrating a novel injurious role of the entire NOSs system in cerebral infarction. Inhibition of the NOSs system may be a novel therapeutic option in the treatment of cerebral infarction.
Author Disclosures: M. Tsutsui: None. H. Kubota: None. K. Noguchi: None. T. Matsuzaki: None. F. Hattori: None. M. Sakanashi: None. M. Kina-Tanada: None. T. Uchida: None. J. Nakasone: None. H. Shimokawa: None. Y. Ohya: None. K. Sugahara: None. M. Kakinohana: None.
- © 2014 by American Heart Association, Inc.