Adiponectin prevents cerebral ischemic injury through endothelial nitric oxide synthase-dependent mechanisms
Adiponectin prevents cerebral ischemic injury through endothelial nitric oxide synthase-dependent mechanisms
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DOI：
10.1161/circulationaha.107.725044
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发表时间：
2008-01-15
期刊：
影响因子：
37.8
通讯作者：
Ouchi, Noriyuki
中科院分区：
文献类型：
--
作者：
Nishimura, Masaki;Izumiya, Yasuhiro;Ouchi, Noriyuki
背景-脂联素是一种脂源性血浆蛋白，对心血管疾病具有有益作用。低水平的血浆脂联素与缺血性中风后死亡率增加有关;然而，脂联素在缺血性中风中的因果作用是unknown.Methods and 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.与WT小鼠相比，APN-KO小鼠在缺血再灌注后表现出脑梗死扩大和神经功能缺损增加。相反，腺病毒介导的脂联素补充显著减少WT和APN-KO小鼠的脑梗死面积。通过激光散斑血流测量法，APN-KO小鼠在缺血期间显示脑血流量减少。免疫组化分析脂联素在短暂性脑缺血状态下共定位于脑血管内皮。与WT小鼠相比，APN-KO小鼠缺血脑组织中内皮型一氧化氮合酶的磷酸化和血浆中一氧化氮代谢产物的产生减弱。腺病毒介导的脂联素给药刺激WT和APN-KO小鼠脑缺血期间内皮型一氧化氮合酶磷酸化和一氧化氮代谢产物。WT和APN-KO小鼠在缺血期间的神经元一氧化氮合酶表达没有差异。腺病毒介导的脂联素的传递并不影响脑梗死的小鼠缺乏内皮型一氧化氮synthes. Conclusions，这些数据提供了因果关系的证据，脂联素通过内皮型一氧化氮合酶依赖的机制发挥脑保护作用。脂联素可能成为预防缺血性卒中的分子靶点。
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.Methods and 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.