标题：Losartan, an angiotensin II type 1 receptor blocker, ameliorates cerebral ischemia-reperfusion injury via PI3K/Akt-mediated eNOS phosphorylation
作者：Liu, Huiqing; Liu, Xiaoqian; Wei, Xinbing; Chen, Lin; Xiang, Yanxiao; Yi, Fan; Zhang, Xiumei
作者机构：[Liu, Huiqing; Liu, Xiaoqian; Wei, Xinbing; Chen, Lin; Xiang, Yanxiao; Yi, Fan; Zhang, Xiumei] Shandong Univ, Sch Med, Dept Pharmacol, Jinan 250012, S 更多
通讯作者地址：[Zhang, XM]Shandong Univ, Sch Med, Dept Pharmacol, 44 Wenhua Xi Rd, Jinan 250012, Shandong, Peoples R China.
来源：BRAIN RESEARCH BULLETIN
关键词：Angiotensin II type 1 receptor; Losartan; Cerebral ischemia-reperfusion; injury; Phosphorylated eNOS; PI3K/Akt signaling
摘要：Angiotensin (Ang) II type 1 receptor blockers (ARBs) have been shown to protect against cerebral ischemia-reperfusion (I/R) injury. However, the mechanism by which ARBs protect brain ischemia injury is still unclear. The aims of this study were to investigate the effects of losartan, an ARB, on the phosphorylation of endothelial nitric oxide synthase (eNOS) in response to focal brain I/R and to determine whether the neuroprotective phosphatidylinositol-3-kinase (PI3K)-Akt signaling pathway is involved. Normotensive Wistar rats were pretreated for 14 days with 5 mg/kg losartan, then subjected to middle cerebral artery occlusion for 2 h followed by reperfusion (MCAO-R). Our results showed that losartan reduced infarct volumes and improved neurobehavioral outcomes in rats subjected to MCAO-R. Losartan pretreatment significantly suppressed an increase in inducible nitric oxide synthase (iNOS) and sustained normal levels of eNOS expression 24 h after MCAO-R injury. Phosphorylated eNOS and Akt levels were much lower than those in the sham group at 24 h after MCAO-R, suggesting that losartan pretreatment significantly preserved eNOS phosphorylation in response to the activated Akt. Moreover, blockade of PI3K activity by wortmannin, totally abolished losartan-induced eNOS phosphorylation, providing the first evidence that losartan stimulates eNOS phosphorylation through PI3K/Akt signaling in the MCAO-R rat model. Our findings provide a mechanistic basis underlying the benefits of using selective ARBs, such as losartan, in the treatment of cerebrovascular disease (C) 2012 Elsevier Inc. All rights reserved.