Role of thrombin-PAR1-PKCθ/δ axis in brain pericytes in thrombin-induced MMP-9 production and blood–brain barrier dysfunction in vitro

Machida, Takashi; Dohgu, Shinya; Takata, Fuyuko; Matsumoto, Junichi; Kimura, Ikuya; Koga, Mariko; Nakamoto, Keiko; Yamauchi, Atsushi; Kataoka, Yasufumi

doi:10.1016/j.neuroscience.2017.03.026

Cited by 61 publications

(38 citation statements)

References 44 publications

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“…Similar result was confirmed by transfecting BMECs with siRNA targeting PKC-β, in which the activation of PKC-β was impeded and the BBB damage was mitigated [35]. A recent study demonstrated that Go6983 decreased the phosphorylation levels of PKCδ and inhibited the release of MMP-9, which suggested that PKC-δ participated in PAR1-mediated MMP-9 release from pericytes, which lead to BBB dysfunction [40]. However, the role of PKC-ε is different from PKC isozymes mentioned above.…”

Section: Cellular Physiology and Biochemistrysupporting

confidence: 57%

“…However, the mechanism by which PKC modulates TJ proteins is still poorly understood. One hypothesis is that PKC may directly regulate the structure and function of TJ proteins, and the other is that PKC may be indirectly altering the TJ proteins by activating a downstream intracellular signaling pathway that in turn directly affects the TJ proteins [40]. Further investigations on the colocalization and distributions of TJ protein after CA and resuscitation with or without H 2 S inhalation will be needed.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

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Hydrogen Sulfide Decreases Blood-Brain Barrier Damage via Regulating Protein Kinase C and Tight Junction After Cardiac Arrest in Rats

Zhu

Feng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hydrogen sulfide (H₂S) can decrease blood-brain barrier (BBB) permeability after cardiac arrest (CA) and resuscitation; however, the underlying mechanisms are not understood clearly. Methods: We investigated the effects of inhalation of H₂S on CA and resuscitation in a rat model of CA. We used Evans blue to detect the integrity of BBB and Western blot to assess the activation of protein kinase c (PKC) isozymes and the expression of Claudin-5, Occludin, and ZO-1. Neurological deficit scales and the 14-days survival rate were measured. Results: We determined that inhalation of 40 p.p.m or 80 p.p.m H₂S significantly decreased brain water content and Evans blue leakage, ameliorated neurologic deficit scale and improved 14-days survival rate. H₂S inhibited the activation of PKC-α, β I, β II and δ, impelled the activation of PKC-ε, and increased the expression of Claudin-5, Occludin and ZO-1. Conclusions: H₂S improved the integrity of BBB, mitigated brain edema; improved neurological outcome and 14-days survival rate in rats after CA and resuscitation. The beneficial effects of H₂S may be associated with inhibiting the activation of PKC-α, β I, β II and δ, promoting the activation of PKC-ε, and increasing the expression of Claudin-5, Occludin and ZO-1.

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Section: Cellular Physiology and Biochemistrysupporting

confidence: 57%

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Hydrogen Sulfide Decreases Blood-Brain Barrier Damage via Regulating Protein Kinase C and Tight Junction After Cardiac Arrest in Rats

Zhu

Feng

et al. 2018

Cell Physiol Biochem

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“…Apoptosis was identified in ECs exposed to I/R injury within just a few minutes [ 7 ]. The endothelial barrier dysfunction and apoptosis have been linked to the activation of protein kinase Cs (PKCs) [ 8 ]. One of the novel PKC isoforms, the PKC delta (PKCδ), was indicated to be associated with the responses to DNA damage [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Baicalin Suppresses Hypoxia-Reoxygenation-Induced Arterial Endothelial Cell Apoptosis via Suppressing PKCδ/p53 Signaling

et al. 2017

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BackgroundThis study was aimed to investigate the protective role of baicalin on vascular endothelium exposed to ischemia reperfusion injury and the involved molecular mechanisms.Material/MethodsCultured human arterial endothelial cells (HAECs) were exposed to hypoxia/deoxygenation (H/R). Cells were also treated with baicalin at serially diluted concentrations. Cells were also treated with PKC activator PEP005 or specific siRNA against protein kinase Cδ (PKCδ). MTT assay was used to evaluate the cell viabilities. Flow cytometry was used to detect cell apoptosis. The protein phosphorylation and expression levels were determined by Western blotting.ResultsPKCδ-siRNA transfection increased cell viabilities and reduced cell apoptosis in HAECs exposed to H/R. Baicalin treatment preserved cell viabilities and reduced apoptosis of H/R-exposed HAECs in a concentration-dependent manner. Baicalin treatment reduced phosphorylation levels of PKCδ and p53, as well as the expression levels of active caspase3 and bax in HAECs exposed to H/R. The treatment of PKC activator PEP005 impaired the protective effects of baicalin in increasing cell viabilities and reducing apoptosis in HAECs exposed to H/R.ConclusionsBaicalin exerts vascular a protective effect on HAECs exposed to H/R by reducing cell apoptosis. The PKCδ/p53 apoptotic signaling pathway was the pharmacological target of baicalin.

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“…Key aspects of the findings made in murine BEC were replicated in human BEC, lending important translational relevance to our studies. Notably, the signaling cascade identified here involving tPA/plasmin, PAR-1 and Ca 2+ in MMP-9 secretion in NF-κB-activated brain endothelial cells ( Fig 8 ) is similar to the cascade involving thrombin, PAR-1 and Ca 2+ in MMP-9 secretion in pericytes and NF-κB-activated monocytes [ 66 , 67 ].…”

Section: Discussionmentioning

confidence: 58%

SUR1-TRPM4 channel activation and phasic secretion of MMP-9 induced by tPA in brain endothelial cells

et al. 2018

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BackgroundHemorrhagic transformation is a major complication of ischemic stroke, is linked to matrix metalloproteinase-9 (MMP-9), and is exacerbated by tissue plasminogen activator (tPA). Cerebral ischemia/reperfusion is characterized by SUR1-TRPM4 (sulfonylurea receptor 1—transient receptor potential melastatin 4) channel upregulation in microvascular endothelium. In humans and rodents with cerebral ischemia/reperfusion (I/R), the SUR1 antagonist, glibenclamide, reduces hemorrhagic transformation and plasma MMP-9, but the mechanism is unknown. We hypothesized that tPA induces protease activated receptor 1 (PAR1)-mediated, Ca2+-dependent phasic secretion of MMP-9 from activated brain endothelium, and that SUR1-TRPM4 is required for this process.MethodsCerebral I/R, of 2 and 4 hours duration, respectively, was obtained using conventional middle cerebral artery occlusion. Immunolabeling was used to quantify p65 nuclear translocation. Murine and human brain endothelial cells (BEC) were studied in vitro, without and with NF-κB activation, using immunoblot, zymography and ELISA, patch clamp electrophysiology, and calcium imaging. Genetic and pharmacological manipulations were used to identify signaling pathways.ResultsCerebral I/R caused prominent nuclear translocation of p65 in microvascular endothelium. NF-κB-activation of BEC caused de novo expression of SUR1-TRPM4 channels. In NF-κB-activated BEC: (i) tPA caused opening of SUR1-TRPM4 channels in a plasmin-, PAR1-, TRPC3- and Ca2+-dependent manner; (ii) tPA caused PAR1-dependent secretion of MMP-9; (iii) tonic secretion of MMP-9 by activated BEC was not influenced by SUR1 inhibition; (iv) phasic secretion of MMP-9 induced by tPA or the PAR1-agonist, TFLLR, required functional SUR1-TRPM4 channels, with inhibition of SUR1 decreasing tPA-induced MMP-9 secretion.ConclusionstPA induces PAR1-mediated, SUR1-TRPM4-dependent, phasic secretion of MMP-9 from activated brain endothelium.

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Role of thrombin-PAR1-PKCθ/δ axis in brain pericytes in thrombin-induced MMP-9 production and blood–brain barrier dysfunction in vitro

Cited by 61 publications

References 44 publications

Hydrogen Sulfide Decreases Blood-Brain Barrier Damage via Regulating Protein Kinase C and Tight Junction After Cardiac Arrest in Rats

Hydrogen Sulfide Decreases Blood-Brain Barrier Damage via Regulating Protein Kinase C and Tight Junction After Cardiac Arrest in Rats

Baicalin Suppresses Hypoxia-Reoxygenation-Induced Arterial Endothelial Cell Apoptosis via Suppressing PKCδ/p53 Signaling

SUR1-TRPM4 channel activation and phasic secretion of MMP-9 induced by tPA in brain endothelial cells

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