• Korean Chemical Engineering Research
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• 제47권4호
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• pp.501-505
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• 2009

본 논문에서는 혈관내피세포에서 활성화된 단백질 C(Activated Protein C, APC)의 항염증 작용에서 수용성 EPCR(Soluble Endothelial Protein C Receptor, sEPCR)의 효과를 관찰하였다. sEPCR은 APC가 매개하는 항염증 작용에 있어 내피세포막의 보호효과를 저해하고, 혈관내피세포에 대한 백혈구의 부착저해 효과를 억제하며, 혈관내피세포를 관통하는 백혈구의 이동을 저해하는 효과를 억제한다. 그리고 흥미롭게도 sEPCR은 내피세포에서 TNF-alpha에 의한 세포부착단백질의 발현을 억제하는 APC의 기전을 저해함으로써 APC가 가지는 항염증 효과를 억제한다. 이것은 APC의 Gla 도메인이 내피세포의 수용체인 EPCR에 결합할 수 있는 부위에 sEPCR이 상호작용함으로써 더 이상 APC이 세포막에 존재하는 EPCR과 결합을 못함으로써 APC의 항염증 작용은 억제되는 것을 의미한다. 이 결과는 향후 중증 패혈증 및 염증질환을 효과적으로 치료할 수 있는 신약개발에 중요한 단서를 제공할 것이고 내피세포에서 아직 명확하게 밝혀지지 않은 APC의 항염증 작용의 기전을 밝히는 데 좋은 정보를 제공할 것이다.

• 생명과학회지
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• 제23권5호
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• pp.650-656
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• 2013

내피세포 단백질 C 수용체(EPCR)가 트롬빈-트롬보모듈린 복합체에 의한 단백질 C (PC) 활성 증가에 중요한 역할을 한다. EPCR의 활성은 ecodomain의 분열과 수용성 단백질(sEPCR)로 분비함으로써 현저하게 변화한다. EPCR의 탈락은 tumor necrosis factor-${\alpha}$ converting enzyme (TACE)에 의해 매개된다. 토마토에서 발견된 라이코펜은 항산화 효과, 항암 효과, 항염증 효과를 가지고 있다. 그러나 EPCR 탈락에서의 라이코펜의 효과는 알려지지 않았다. 우리는 라이코펜이 PMA, TNF-${\alpha}$, IL-$1{\beta}$와 CLP에 의해 유도된 EPCR 탈락에 미치는 영향을 연구했다. 그 결과, 라이코펜은 TACE의 발현을 억제시켜 PMA, TNF-${\alpha}$, IL-$1{\beta}$와 CLP에 의해 매개된 EPCR 탈락을 저해함을 보여준다. 또한 라이코펜은 PMA가 유발한 p38, ERK1/2, JNK의 인산화를 감소시켰다. 이러한 결과를 토대로, 라이코펜은 EPCR 탈락의 저해를 통해 다양한 중증 혈관 염증 질병 치료를 위한 후보 물질이 될 수 있을 것이다.

• BMB Reports
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• 제47권6호
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• pp.336-341
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• 2014

Endothelial cell protein C receptor (EPCR) plays important roles in blood coagulation and inflammation. EPCR activity is markedly changed by ectodomain cleavage and release as the soluble EPCR. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-${\alpha}$ converting enzyme (TACE). Oroxylin A (OroA), a major component of Scutellaria baicalensis Georgi, is known to exhibit anti-angiogenic, antiinflammation, and anti-invasive activities. However, little is known about the effects of OroA on EPCR shedding. Data showed that OroA induced potent inhibition of phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-${\alpha}$, interleukin (IL)-$1{\beta}$ and on cecal ligation and puncture (CLP)-induced EPCR shedding through suppression of TACE expression and activity. In addition, treatment with OroA resulted in reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate the potential of OroA as an anti-sEPCR shedding reagent against PMA and CLP-mediated EPCR shedding.

• BMB Reports
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• 제48권11호
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• pp.624-629
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• 2015

Lysozyme protects us from the ever-present danger of bacterial infection and binds to bacterial lipopolysaccharide (LPS) with high affinity. Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). However, little is known about the effects of lysozyme on EPCR shedding. We investigated this issue by monitoring the effects of lysozyme on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-α-, interleukin (IL)-1βand cecal ligation and puncture (CLP)-mediated EPCR shedding and underlying mechanism. Data demonstrate that lysozyme induced potent inhibition of PMA-, TNF-α-, IL-1β-, and CLP-induced EPCR shedding. Lysozyme also inhibited the expression and activity of PMA-induced TACE in endothelial cells. These results demonstrate the potential of lysozyme as an anti-EPCR shedding reagent against PMA-mediated and CLP-mediated EPCR shedding.

• 한국환경과학회:학술대회논문집
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• 한국환경과학회 2008년도 추계학술발표회 발표논문집
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• pp.538-544
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• 2008

Activated protein C (APC) is thought to exert antiinflammatory activities through the endothelial protein C receptor (EPCR)-dependent cleavage of protease activated receptor 1 (PAR-1) in endothelial cells. Since thrombin cleaves PAR-1 with $\sim$3-4-orders of magnitude higher efficiency, and PAR-1 is a target for proinflammatory activities of thrombin, it is not understood how APC can elicit protective responses through the cleavage of PAR-1. In this study, we demonstrate that EPCR is associated with caveolin-1 in endothelial lipid rafts, but its occupancy by protein C leads to its dissociation from caveolin-1 and subsequent recruitment of PAR-1 to protective signaling pathways through the coupling of PAR-1 to Gi-protein. When EPCR is bound by protein C, the PAR-1-dependent protective response in endothelial cells can be mediated by either thrombin or APC. These results provide a new paradigm for understanding the mechanism through which PAR-1 and EPCR participate in cellular signaling events in endothelial cells.

• BMB Reports
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• 제46권11호
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• pp.544-549
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• 2013

High mobility group box 1 (HMGB1) is involved in the pathogenesis of vascular diseases. Unlike activated protein C (APC), the activation of PAR-1 by thrombin is known to elicit proinflammatory responses. To determine whether the occupancy of EPCR by the Gla-domain of APC is responsible for the PAR-1-dependent antiinflammatory activity of the protease, we pretreated HUVECs with the PC zymogen and then activated PAR-1 with thrombin. It was found that thrombin downregulates the HMGB1-mediated induction of both TNF-${\alpha}$ and IL-6 and inhibits the activation of both p38 MAPK and NF-${\kappa}B$ in HUVECs pretreated with PC. Furthermore, thrombin inhibited HMGB1-mediated hyperpermeability and leukocyte adhesion/migration by inhibiting the expression of cell adhesion molecules in HUVECs if EPCR was occupied. Collectively, these results suggest the concept that thrombin can initiate proinflammatory responses in vascular endothelial cells through the activation of PAR-1 may not hold true for normal vessels expressing EPCR under in vivo conditions.