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Isoflurane Postconditioning Inhibits tPA-Induced Matrix Metalloproteinases Activation After Hypoxic Injury via Low-Density Lipoprotein Receptor-Related Protein and Extracellular Signal-Regulated Kinase Pathway

 So Yeon Kim  ;  So Yeong Cheon  ;  Eun Jung Kim  ;  Jae Hoon Lee  ;  Eun Hee Kam  ;  Jeong Min Kim  ;  Miran Park  ;  Bon-Nyeo Koo 
 Neurochemical Research, Vol.42(5) : 1533-1542, 2017 
Journal Title
 Neurochemical Research 
Issue Date
Anesthetics, Inhalation/pharmacology ; Animals ; Cell Hypoxia/drug effects ; Cell Hypoxia/physiology ; Cell Line ; Cell Survival/drug effects ; Cell Survival/physiology ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Enzyme Activation/drug effects ; Enzyme Activation/physiology ; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors ; Extracellular Signal-Regulated MAP Kinases/metabolism* ; Ischemic Postconditioning/methods* ; Isoflurane/pharmacology* ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism* ; Matrix Metalloproteinases/metabolism* ; Mice ; Tissue Plasminogen Activator/antagonists & inhibitors ; Tissue Plasminogen Activator/pharmacology*
Extracellular signal-regulated kinase ; Hypoxia ; Isoflurane ; Low-density lipoprotein receptor-related protein ; Matrix metalloproteinase ; Tissue plasminogen activator
Tissue plasminogen activator (tPA) is the only recommended pharmacological treatment for acute ischemic stroke. However, tPA can induce intracerebral hemorrhage by blood-brain barrier breakdown through an increase in matrix metalloproteinases (MMPs). Previously, we showed that isoflurane postconditioning reduced intracranial hemorrhage following tPA treatment after cerebral ischemia. Here, we investigated the mechanism by which isoflurane postconditioning reduces tPA-induced MMP-2 and MMP-9 activation following hypoxia/reoxygenation (H/R) in brain endothelial cells. Mouse brain endothelial cells (bEnd.3) were exposed to 6 h of oxygen-glucose deprivation and 3 h of reoxygenation with tPA. Cells were treated with isoflurane for 1 h of the reoxygenation condition and the effect of isoflurane postconditioning on MMP-2 and MMP-9 activation was assessed. Involvement of low-density lipoprotein receptor-related protein (LRP), which is a receptor for tPA, and the extracellular signal-regulated kinase (ERK) and NF-κB pathway in isoflurane postconditioning was assessed using LRP inhibitor (receptor-associated protein, RAP) and ERK-1/2 inhibitor (PD98059). Isoflurane postconditioning decreased tPA-induced MMP-2 and MMP-9 activation under H/R. tPA treatment under H/R increased expression of LRP and the active form of NF-κB. Isoflurane postconditioning suppressed LRP expression, increased ERK-1/2 activation, and suppressed MMP-2 and MMP-9 activation, comparable to the effect of RAP. Activation of ERK-1/2, inhibition of NF-κB activation, and suppression of MMP-2 and MMP-9 activation by isoflurane postconditioning were abolished with PD98059 treatment. These finding indicate that isoflurane postconditioning inhibits tPA-induced MMP-2 and MMP-9 activation following H/R via the LRP/ERK/NF-κB pathway in bEnd.3.
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1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers
Yonsei Authors
구본녀(Koo, Bon-Nyeo) ORCID logo https://orcid.org/0000-0002-3189-1673
김소연(Kim, So Yeon) ORCID logo https://orcid.org/0000-0001-5352-157X
김은정(Kim, Eun Jung) ORCID logo https://orcid.org/0000-0002-5693-1336
김정민(Kim, Jeongmin) ORCID logo https://orcid.org/0000-0002-0468-8012
박미란(Park, Miran)
이재훈(Lee, Jae Hoon) ORCID logo https://orcid.org/0000-0001-6679-2782
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