title: Angiotensin-(1-7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways.
abstract: Angiotensin (Ang) II, the main effector of the renin-angiotensin system, has been implicated in the pathogenesis of vascular diseases. Ang-(1-7) binds to the G protein-coupled Mas receptor (MasR) and can exert vasoprotective effects. We investigated the effects and underlying mechanisms of Ang-(1-7) on Ang II-induced dysfunction and oxidative stress in human brain microvascular endothelial cells (HbmECs). The pro-apoptotic activity, reactive oxygen species (ROS) and nitric oxide (NO) productions in HbmECs were measured. The protein expressions of nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), serine/threonine kinase (Akt), endothelial nitric oxide synthase (eNOS) and their phosphorylated forms (p-Akt and p-eNOS) were examined by western blot. MasR antagonist and phosphatidylinositol-3-kinase (PI3K) inhibitor were used for receptor/pathway verification. We found that Ang-(1-7) suppressed Ang II-induced pro-apoptotic activity, ROS over-production and NO reduction in HbmECs, which were abolished by MasR antagonist. In addition, Ang-(1-7) down-regulated the expression of Nox2, and up-regulated the ratios of p-Akt/Akt and its downstream p-eNOS/eNOS in HbmECs. Exposure to PI3K inhibitor partially abrogated Ang-(1-7)-mediated protective effects in HbmECs. Our data suggests that Ang-(1-7)/MasR axis protects HbmECs from Ang II-induced dysfunction and oxidative stress via inhibition of Nox2/ROS and activation of PI3K/NO pathways.
authors.affiliation: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Xiaotang
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Huilai
authors.initials: H
authors.lastname: Miao
authors.affiliation: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Jinju
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Langni
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Surgery, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zeng
authors.affiliation: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA. Electronic address: yanfang.chen@wright.edu.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA; Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, China. Electronic address: ji.bihl@wright.edu.
authors.forename: Ji C
authors.initials: JC
authors.lastname: Bihl
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000803:Angiotensin I; D000804:Angiotensin II; D019255:NADPH Oxidases; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C000715470:MAS1 protein, human; C496314:NOS3 protein, human; C118790:angiotensin I (1-7)
keywords: Ang II; Ang-(1–7); Cerebral endothelial cells; Oxidative stress