A novel cell-permeable antioxidant peptide, SS31, attenuates ischemic brain injury by down-regulating CD36
A novel cell-permeable antioxidant peptide, SS31, attenuates ischemic brain injury by down-regulating CD36
复制标题
DOI：
10.1074/jbc.m609388200
复制
发表时间：
2007-02-16
影响因子：
4.8
通讯作者：
Pinto, John T.
中科院分区：
文献类型：
--
作者：
Cho, Sunghee;Szeto, Hazel H.;Pinto, John T.
氧化应激与缺血再灌注损伤的发病机制有关。最近，我们证明了B类清除率受体CD36的激活介导了脑缺血中自由基的产生和组织损伤(1)。氧化低密度脂蛋白（oxLDL）是与CD36结合并在急性脑梗死中升高的配体之一。SS31是一种细胞渗透性抗氧化肽，可减少细胞内自由基，抑制LDL氧化/脂质过氧化(2)。目前的研究旨在研究SS31治疗是否能使缺血诱导的氧化还原变化正常化，并减轻cd36介导的组织损伤。C57BL/6小鼠短暂性大脑中动脉闭塞（MCAO）。用生理盐水或SS31治疗的动物测量氧化还原状态和梗死体积。缺血/再灌注引起的氧化应激导致同侧皮质和纹状体谷胱甘肽（GSH）浓度严重降低。再灌注后立即用SS31治疗小鼠可显著减轻缺血诱导的皮质谷胱甘肽耗竭并减少梗死面积。相比之下，SS31在CD36敲除小鼠中不存在保护作用，表明SS31是通过抑制CD36起作用的。用SS31治疗C57BL/6小鼠可降低脑缺血后和小鼠腹腔巨噬细胞（MPM）中CD36的表达。进一步的体外研究表明，SS31可以减弱氧化ldl诱导的MPM中CD36的表达和泡沫细胞的形成。这些体内和体外研究表明，新型抗氧化肽下调CD36可能是治疗缺血性卒中患者的有效策略。
Oxidative stress is implicated in the pathogenesis of ischemia/reperfusion injury. Recently, we demonstrated that activation of CD36, a class B scavenger receptor, mediates free radical production and tissue injury in cerebral ischemia (1). Oxidized low density lipoproteins (oxLDL) are among the ligands that bind to CD36 and are elevated in acute cerebral infarction. SS31 is a cell-permeable antioxidant peptide that reduces intracellular free radicals and inhibits LDL oxidation/lipid peroxidation (2). The current study was designed to investigate whether treatment with SS31 normalizes ischemia-induced redox changes and attenuates CD36-mediated tissue injury. C57BL/6 mice were subjected to transient middle cerebral artery occlusion (MCAO). Redox status and infarct volume were measured in animals treated with either saline or SS31. Oxidative stress induced by ischemia/reperfusion profoundly depleted glutathione (GSH) concentrations in the ipsilateral cortex and striatum. Treating mice with SS31 immediately after reperfusion significantly attenuated ischemia-induced GSH depletion in the cortex and reduced infarct size. By contrast, the protective effect of SS31 was absent in CD36 knock-out mice, indicating that SS31 is acting through inhibition of CD36. Treating C57BL/6 mice with SS31 reduced CD36 expression in postischemic brain and mouse peritoneal macrophages (MPM). Further in vitro studies revealed that SS31 attenuated oxLDL-induced CD36 expression and foam cell formation in MPM. These in vivo and in vitro studies indicate that the down-regulation of CD36 by novel class antioxidant peptides may be a useful strategy to treat ischemic stroke victims.