title: Losartan, an angiotensin II type 1 receptor blocker, ameliorates cerebral ischemia-reperfusion injury via PI3K/Akt-mediated eNOS phosphorylation.
abstract: 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 5mg/kg losartan, then subjected to middle cerebral artery occlusion for 2h 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 24h after MCAO-R injury. Phosphorylated eNOS and Akt levels were much lower than those in the sham group at 24h 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.
authors: Department of Pharmacology, Shandong University School of Medicine, Jinan, Shandong, PR China.
authors: Huiqing
authors: H
authors: Liu
authors: Xiaoqian
authors: X
authors: Liu
authors: Xinbing
authors: X
authors: Wei
authors: Lin
authors: L
authors: Chen
authors: Yanxiao
authors: Y
authors: Xiang
authors: Fan
authors: F
authors: Yi
authors: Xiumei
authors: X
authors: Zhang
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D019808:Losartan