Cytokine upregulation of proteinase‐activated‐receptors 2 and 4 expression mediated by p38 MAP kinase and inhibitory kappa B kinase <i>β</i> in human endothelial cells

Ritchie, E; Saka, Masako; Mackenzie, Christopher; Drummond, Robert M.; Wheeler‐Jones, Caroline P.D.; Kanke, Toru; Plevin, Robin

doi:10.1038/sj.bjp.0707150

Cited by 70 publications

(56 citation statements)

References 57 publications

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“…A similar pattern was observed in SMCs from human coronary artery. Our finding reflects reports in endothelial cells that PARs are subject to differen- tial regulation 20,21 and raises the interesting possibility that individual PARs play distinct roles in various pathological conditions. The increase in PAR-4 mRNA by high glucose was sustained over the 96 hours of incubation and accompanied by increased PAR-4 protein and cell surface expression.…”

Section: Discussionsupporting

confidence: 69%

“…Vascular PAR-3 is thought to act predominantly as a cofactor for PAR-1 in endothelium, 18 whereas PAR-4 is reportedly involved in myocardial reper- fusion injury 19 and in the endothelial response to inflammatory challenge. 20,21 In the present study in human saphenous vein SMCs, elevated glucose led to a rapid and sustained induction of PAR-4 mRNA, whereas neither PAR-1 nor PAR-3 was significantly influenced. A similar pattern was observed in SMCs from human coronary artery.…”

Section: Discussionmentioning

confidence: 89%

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High Glucose Enhances Thrombin Responses via Protease-Activated Receptor-4 in Human Vascular Smooth Muscle Cells

Dangwal

Rauch

Gensch

et al. 2011

ATVB

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Objective-Diabetes is associated with vascular remodeling and increased thrombin generation. Thrombin promotes vascular smooth muscle cell (SMC) mitogenesis and migration via protease-activated receptors (PAR)-1, PAR-3, and PAR-4. We investigated the effect of high glucose on expression and function of vascular thrombin receptors. Methods and Results-In human vascular SMCs, high glucose (25 versus 5.5 mmol/L) induced a rapid and sustained increase in PAR-4 mRNA, protein, and cell surface expression. PAR-1 and PAR-3 expression were not changed. High glucose pretreatment (48 hours) enhanced thrombin or PAR-4 -activating peptide but not PAR-1-activating peptide evoked intracellular calcium mobilization, migration, and tumor necrosis factor ␣ gene expression. This enhancement of thrombinstimulated migration and gene expression by high glucose was abolished by endogenous PAR-4 knockdown. PAR-4 regulation was prevented by inhibition of protein kinase (PK)C-␤ and -␦ isoforms or nuclear factor (NF)B. Nuclear translocation of NFB in high glucose-stimulated SMCs led to PKC-dependent NFB binding to the PAR-4 promoter in a chromatin immunoprecipitation assay. Furthermore, in situ hybridization and immunohistochemistry confirmed high abundance of PAR-4 in human diabetic vessels as compared with nondiabetic vessels. Key Words: diabetes mellitus Ⅲ thrombin Ⅲ vascular muscle Ⅲ protease-activated receptors C hronically elevated plasma glucose levels in diabetes are associated with cardiovascular complications such as vascular remodeling and poor outcome after revascularization. 1,2 At the cellular level, hyperglycemia is a potent stimulus for the proliferation and migration of vascular smooth muscle cells (SMCs), 3 which are major factors contributing to vascular remodeling and accelerated atherosclerosis. 4 In addition, diabetes represents a hypercoagulable state associated with enhanced thrombin generation and increased risk of thrombotic complications. 5 Thrombin is the central component of the coagulation cascade that becomes activated when vascular injury allows contact between blood-borne components and tissue factor-expressing cells such as fibroblasts and SMCs. 6 However, the overwhelming majority of total thrombin generated is released by the thrombus after clotting is completed, 6,7 indicating functions beyond coagulation. Conclusion-HighThrombin can exert direct coagulation-independent actions such as SMC migration and proliferation through activation of a unique family of G protein-coupled receptors, the protease-activated receptors (PARs). 8 PARs are activated through proteolytic cleavage of the extracellular N terminus, which unmasks a new N terminus that acts as a tethered ligand to autoactivate the receptor. 9 Synthetic hexapeptides mimicking this tethered ligand can elicit most of the biological actions of thrombin independently of receptor cleavage. Of the 4 PARs identified to date, PAR-1, PAR-3, and PAR-4 are activated by thrombin, whereas another receptor, PAR-2, is activated by other proteases such as activa...

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 89%

High Glucose Enhances Thrombin Responses via Protease-Activated Receptor-4 in Human Vascular Smooth Muscle Cells

Dangwal

Rauch

Gensch

et al. 2011

ATVB

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“…PAR2 is activated in response to the partial proteolytic cleavage of the extracellular domain by serine proteases under the influence of p38 MAP (mitogen-activated protein) kinase and by the NFκB signalling pathway, including the potentially divergent roles of the kinases inhibitory kappa B kinases (IKK)-α and -β (Ritchie et al, 2007). Inflammatory cytokines (IL-1α, TNF-α) increase mRNA expression of Par2 in disorders (Seo et al, 2011;Kamath et al, 2001;Ritchie et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Par2 gene (encodes proteinase-activated receptor 2 (PAR2), subgroup of G-protein coupled receptor family) is highly expressed in different pathologies of GIT (Seo et al, 2011;Kamath et al, 2001;Ritchie et al, 2007). PAR2 is activated in response to the partial proteolytic cleavage of the extracellular domain by serine proteases under the influence of p38 MAP (mitogen-activated protein) kinase and by the NFκB signalling pathway, including the potentially divergent roles of the kinases inhibitory kappa B kinases (IKK)-α and -β (Ritchie et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The impact of oxidative stress on Par2, Ptgs2 genes expression in rat duodenal epithelial cells under conditions of prolonged gastric hypochlorhydria and with administration of multiprobiotic

Dranitsina¹,

Dvorshchenko²,

Grebinyk³

et al. 2016

J App Pharm Sci

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Development of dysbiosis is a key consequence of long hypoacidity, in which there is colonization of the gastrointestinal tract by pathogenic microflora that forms source of sustainable endogenous infection and leads to inflammation. The prevalence of free-radical processes of antioxidant defense system is an important pathogenetic link in the origin and development of various disorders. Because reactive oxygen species are important for transcription of Ptgs2 gene, the relationship between oxidative stress, antioxidant element and PAR2-mediated signaling pathways may take place under conditions of dysbiotic changes due to hypochlorhydria. To evaluate the intensity of free radical processes and their impact on Par2, Ptgs2 genes expression in rat duodenal epithelial cells under conditions of prolonged gastric hypochlorhydria and with administration of multi-probiotic. Four experimental groups were created with 8 rats in each. One group was a control, while others were injected with acid suppressant omeprazole or multi-strain probiotic preparation or with both compounds simultaneously for 28 days. Protein oxidative modification products, free SH-groups, metallothioneins content were measured in villus and crypt epithelial cells with standard biochemical assays. Level of Par2, Ptgs2 genes mRNA was determined with semi-quantitative RT-PCR. Prolonged inhibition of acid secretion in stomach was accompanied by significant elevation of free radical processes (intensification of protein oxidative modification, free SH-groups pool reduction, changes of metallothioneins concentration) and elevation of Par2 and Ptgs2 genes expression levels in rat duodenal epithelial cells. Reduction of free radical processes intensity; restoration of redox balance and the normalization of Par2, Ptgs2 gene expression pattern in the duodenum upon the simultaneous administration of the multi-probiotic Symbiter were observed. Par2 overexpression leads to activation Ptgs2 on the background of free radical processes over the antioxidant defense system in the development of inflammation in the duodenum through dysbiotic changes in the conditions of prolonged hypochlorhydria.

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“…As we know, resting ECs can be mainly activated by TNF-α and IL-1β inducing to upregulate the expression level of the cytokine and cell adhesion moleculars (CAMs) via the NF-κB pathway (Modur et al, 1996;Dechanet et al, 1997;Stehlik et al, 1998;Gawaz et al, 2002;Zhou et al, 2007). Study on gene modification of ECs or other cells lines mediated by replication-defective adenovirus vectors has been broadly applied in many aspects including protein expression and RNA silence (Lin et al, 2004;Kim et al, 2007;Ritchie et al, 2007). A study showed that adenovirus vectors can stimulate maturation of dendritic cells, on which the CD40 protein expression was obviously upregulated (Morelli et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Adenovirus vectors can induce activation of endothelial cells: CD40-CD40L interactions partly participate in the endothelial cells activation induced by adenovirus vectors in an NF-kappaB-dependent manner

Li¹,

Xue²,

Tian³

et al. 2011

Afr. J. Biotechnol.

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Replication-defective adenovirus vector without both E1 and E3 is one of the most popular tools in transgenic therapies. However, more attention should be paid to adenovirus vectors mediated-gene modified study on endothelial cells (ECs). To verify the possible danger in that process, we explored the effect of adenovirus on ECs in this study. By using western blot analysis, we showed that the level of both CD40 and CD40L on human umbilical vein endothelial cells (HUVECs) were upregraduated by adenovirus vector infection at 100 multiplicity of infection (MOI). The activation of ECs induced by adenovirus vector infection at MOI 100 can be partly inhibited by a blockade of CD40/CD40L interactions by using the recombinant adenovirus Ad-sCD40LIg or an anti-CD40L monoclonal antibody (mAb) in vitro. On ECs, blockade of CD40/CD40L decreased the expression of IL (interleukin)-6, IL-8 and intercellular adhesion molecule (ICAM) in adenovirus vector-induced cells. In electrophoretic mobility shift assay (EMSA), both Ad-sCD40LIg and anti-CD40L mAb can attenuate the activity of NF-kappaB (NF-κB) pathway contributing to the activation of ECs, which indicated that CD40-CD40L interactions played significant role in the activation of ECs induced by adenovirus vectors via an NF-κB pathway. Our study provide evidences for a supplementary mechanism of the ECs activation induced by adenovirus vector infection and suggests that CD40-CD40L interactions partly participate in the ECs activation induced by adenovirus vectors in an NF-κB-dependent manner.

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Cytokine upregulation of proteinase‐activated‐receptors 2 and 4 expression mediated by p38 MAP kinase and inhibitory kappa B kinase β in human endothelial cells

Cited by 70 publications

References 57 publications

High Glucose Enhances Thrombin Responses via Protease-Activated Receptor-4 in Human Vascular Smooth Muscle Cells

High Glucose Enhances Thrombin Responses via Protease-Activated Receptor-4 in Human Vascular Smooth Muscle Cells

The impact of oxidative stress on Par2, Ptgs2 genes expression in rat duodenal epithelial cells under conditions of prolonged gastric hypochlorhydria and with administration of multiprobiotic

Adenovirus vectors can induce activation of endothelial cells: CD40-CD40L interactions partly participate in the endothelial cells activation induced by adenovirus vectors in an NF-kappaB-dependent manner

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