title: Isoflurane Postconditioning Inhibits tPA-Induced Matrix Metalloproteinases Activation After Hypoxic Injury via Low-Density Lipoprotein Receptor-Related Protein and Extracellular Signal-Regulated Kinase Pathway.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
authors.forename: So Yeong
authors.initials: SY
authors.lastname: Cheon
authors.affiliation: Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Kam
authors.affiliation: Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
authors.forename: Jeong Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
authors.forename: Miran
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. KOOBN@yuhs.ac.
authors.forename: Bon-Nyeo
authors.initials: BN
authors.lastname: Koo
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057775:Ischemic Postconditioning / Q000379:methods*; D007530:Isoflurane / Q000494:pharmacology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D018685:Anesthetics, Inhalation; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D007530:Isoflurane; D048049:Extracellular Signal-Regulated MAP Kinases; D010959:Tissue Plasminogen Activator; D020782:Matrix Metalloproteinases
keywords: Extracellular signal-regulated kinase; Hypoxia; Isoflurane; Low-density lipoprotein receptor-related protein; Matrix metalloproteinase; Tissue plasminogen activator