Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5737694 | Neuroscience | 2017 | 12 Pages |
Abstract
Thrombin, an essential component in the coagulation cascade, participates in the pathogenesis of brain diseases, such as ischemic stroke, intracerebral hemorrhage, Alzheimer's disease and Parkinson's disease through blood-brain barrier (BBB) dysfunction. It is thought that the thrombin-matrix metalloproteinase (MMP)-9 axis is an important process in the pathogenesis of neurovascular disease, such as BBB dysfunction. We recently reported that brain pericytes are the most MMP-9-releasing cells in response to thrombin stimulation among the BBB-constituting cells. This thrombin-induced MMP-9 release is partially due to protease-activated receptor (PAR1), one of the specific thrombin receptors. Then, we evaluated the intracellular signaling pathways involved in MMP-9 release and the contribution of thrombin-reactive brain pericytes to BBB dysfunction. PKC activator evoked MMP-9 release from brain pericytes. The thrombin-induced MMP-9 release was inhibited by U0126, LY294002, Go6976, and Go6983. However, Go6976 decreased phosphorylation levels of PKCθ and Akt, and Go6983 decreased phosphorylation levels of PKCδ and extracellular signal-regulated kinase (ERK). Additionally, treatment of pericytes with thrombin or PAR1-activating peptide stimulated PKCδ/θ signaling. These substances impaired brain endothelial barrier function in the presence of brain pericytes. Brain pericytes function through two independent downstream signaling pathways via PAR1 activation to release MMP-9 in response to thrombin - the PKCθ-Akt pathway and the PKCδ-ERK1/2 pathway. These pathways participate in PAR1-mediated MMP-9 release from pericytes, which leads to BBB dysfunction. Brain pericytes and their specific signaling pathways could provide novel therapeutic targets for thrombin-induced neurovascular diseases.
Keywords
Rat brain endothelial cellPKCBMECphorbol 12-myristate 13-acetatePericyteERKMMP-9In vitro BBB modelRBECDMEMJnkHEPESFBS4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidc-Jun N-terminal kinasePMAMAPKEDTAEthylenediaminetetraacetic acidAlzheimer’s diseaseParkinson’s diseaseThrombinParintracerebral hemorrhageBlood–brain barrierBBBfetal bovine serumbrain microvascular endothelial cellCell signalingactivating peptideSodium fluoresceinMatrix metalloproteinase-9Dulbecco’s modified eagle’s mediumICHPermeabilityProtein kinase Cmitogen-activated protein kinaseextracellular signal-regulated kinaseprotease-activated receptor
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Authors
Takashi Machida, Shinya Dohgu, Fuyuko Takata, Junichi Matsumoto, Ikuya Kimura, Mariko Koga, Keiko Nakamoto, Atsushi Yamauchi, Yasufumi Kataoka,