| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2531522 | European Journal of Pharmacology | 2015 | 7 Pages |
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.
