title: Ang-(1-7) exerts protective role in blood-brain barrier damage by the balance of TIMP-1/MMP-9.
abstract: Cerebrovascular disease (CVD) ranks as the top three health risks, specially cerebral ischemia characterized with the damage of blood-brain barrier (BBB). The angiotensin Ang-(1-7) was proven to have a protective effect on cerebrovascular diseases. However, its role on blood-brain barrier and the underlying molecular mechanism remains unclear. In this study, Ang-(1-7) significantly relieved damage of ischemia reperfusion injury on blood-brain barrier in cerebral ischemia reperfusion injury (IRI) rats. Furthermore, its treatment attenuated BBB permeability and brain edema. Similarly, Ang-(1-7) also decreased the barrier permeability of brain endothelial cell line RBE4. Further analysis showed that Ang-(1-7) could effectively restore tight junction protein (claudin-5 and zonula occludens ZO-1) expression levels both in IRI-rats and hypoxia-induced RBE4 cells. Furthermore, Ang-(1-7) stimulation down-regulated hypoxia-induced matrix metalloproteinase-9 (MMP-9) levels, whose silencing with (matrix metalloproteinase-9 hemopexin domain) MMP9-PEX inhibitor significantly increased the expression of claudin-5 and ZO-1. Further mechanism analysis demonstrated that Ang-(1-7) might junction protein levels by tissue inhibitor of metalloproteinase 1 (TIMP1)-MMP9 pathway, because Ang-(1-7) enhanced TIMP1 expression, whose silencing obviously attenuated the inhibitor effect of Ang-(1-7) on MMP-9 levels and decreased Ang-(1-7)-triggered increase in claudin-5 and ZO-1. Together, this study demonstrated a protective role of Ang-(1-7) in IRI-induced blood-brain barrier damage by TIMP1-MMP9-regulated tight junction protein expression. Accordingly, Ang-(1-7) may become a promising therapeutic agent against IRI and its complications.
authors.affiliation: Department of Encephalopathy, The First Affiliated Hospital of Henan University of TCM, Zhengzhou, Henan 450000, China.
authors.forename: Jitao
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Encephalopathy, The First Affiliated Hospital of Henan University of TCM, Zhengzhou, Henan 450000, China.
authors.forename: Duo
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Encephalopathy, The First Affiliated Hospital of Henan University of TCM, Zhengzhou, Henan 450000, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Encephalopathy, The First Affiliated Hospital of Henan University of TCM, Zhengzhou, Henan 450000, China. Electronic address: danwanghn@163.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D062725:Tight Junction Proteins / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D062725:Tight Junction Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D000803:Angiotensin I; D020780:Matrix Metalloproteinase 9; C118790:angiotensin I (1-7)
keywords: Ang-(1–7); Angiotensin-(1–7) (PubChem CID: 123805); Blood–brain barrier; Claudin-5; MMP-9; TIMP-1; ZO-1