title: Adiponectin prevents cerebral ischemic injury through endothelial nitric oxide synthase dependent mechanisms.
abstract: BACKGROUND
  Adiponectin is a fat-derived plasma protein that has beneficial actions on cardiovascular disorders. A low level of plasma adiponectin is associated with increased mortality after ischemic stroke; however, the causal role of adiponectin in ischemic stroke is unknown.
  
  
  RESULTS
  To explore the role of adiponectin in the development of acute cerebral injury, we subjected adiponectin-deficient (APN-KO) and wild-type (WT) mice to 1 hour of middle cerebral artery occlusion followed by 23 hours of reperfusion. APN-KO mice exhibited enlarged brain infarction and increased neurological deficits after ischemia-reperfusion compared with WT mice. Conversely, adenovirus-mediated supplementation of adiponectin significantly reduced cerebral infarct size in WT and APN-KO mice. APN-KO mice showed decreased cerebral blood flow during ischemia by laser speckle flowmetry methods. Adiponectin colocalized within the cerebral vascular endothelium under transient ischemic conditions by immunohistochemical analysis. Phosphorylation of endothelial nitric oxide synthase in ischemic brain tissues and the production of nitric oxide metabolites in plasma were attenuated in APN-KO mice compared with WT mice. Adenovirus-mediated administration of adiponectin stimulated endothelial nitric oxide synthase phosphorylation and nitric oxide metabolites during cerebral ischemia in both WT and APN-KO mice. Neuronal nitric oxide synthase expression during ischemia did not differ between WT and APN-KO mice. Adenovirus-mediated delivery of adiponectin did not affect brain infarction in mice deficient in endothelial nitric oxide synthase.
  
  
  CONCLUSIONS
  These data provide causal evidence that adiponectin exerts a cerebroprotective action through an endothelial nitric oxide synthase-dependent mechanism. Adiponectin could represent a molecular target for the prevention of ischemic stroke.
authors.affiliation: Stroke and Neurovascular Regulation Laboratory, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Izumiya
authors.forename: Akiko
authors.initials: A
authors.lastname: Higuchi
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.forename: Jianhua
authors.initials: J
authors.lastname: Qiu
authors.forename: Chiho
authors.initials: C
authors.lastname: Kudo
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moskowitz
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
mesh_terms: D052242:Adiponectin / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D002545:Brain Ischemia; D004730:Endothelium, Vascular / Q000737:chemistry; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D020768:Middle Cerebral Artery; D009569:Nitric Oxide / Q000032:analysis; D052248:Nitric Oxide Synthase Type I / Q000032:analysis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D020521:Stroke
chemical_list: D052242:Adiponectin; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III