Gene Expression Profile of Antithrombotic Protein C Defines New Mechanisms Modulating Inflammation and Apoptosis

Joyce, David E.; Gelbert, Larry; Ciaccia, Angelina V.; DeHoff, Brad; Grinnell, Brian W.

doi:10.1074/jbc.c100017200

Cited by 609 publications

(536 citation statements)

References 41 publications

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“…However, through in vitro and in vivo models, APC has been shown to not only regulate coagulation in the microvasculature but also affect inflammation, apoptosis, proliferation, and angiogenesis. APC inhibits apoptosis through upregulation of anti-apoptotic Bcl-2 [19][20][21], and downregulation of p53, Bax [20,21], and caspases 3 [20][21][22], 8, and 9 [21,22] all through interactions with EPCR and protease-activated receptors (PAR). Using a murine focal ischemic stroke model, human and mouse APC treatment restored blood flow, reduced infarct volume and edema, eliminated neutrophil infiltration, and reduced fibrin deposition [20][21][22][23][24], all mediated through EPCR [20], PAR-1 [20,21], and PAR-3 [21].…”

Section: Introductionmentioning

confidence: 99%

Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

Beaulieu

Church

2007

Experimental Cell Research

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Activated protein C (APC) is a serine protease that regulates thrombin (IIa) production through inactivation of blood coagulation factors Va and VIIIa. APC also has non-hemostatic functions related to inflammation, proliferation, and apoptosis through various mechanisms. Using two breast cancer cell lines, MDA-MB-231 and MDA-MB-435, we investigated the role of APC in cell chemotaxis and invasion. Treatment of cells with increasing APC concentrations (1-50 μg/ml) increased invasion and chemotaxis in a concentration-dependent manner. Only the active form of APC increased invasion and chemotaxis of the MDA-MB-231 cells when compared to 3 inactive APC derivatives. Using a modified "checkerboard" analysis, APC was shown to only affect migration when plated with the cells; therefore, APC is not a chemoattractant. Blocking antibodies to endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1) attenuated the effects of APC on chemotaxis in the MDA-MB-231 cells. Finally, treatment of the MDA-MB-231 cells with the proliferation inhibitor, Na butyrate, showed that APC did not increase migration by increasing cell number. Therefore, APC increases invasion and chemotaxis of cells by binding to the cell surface and activating specific signaling pathways through EPCR and PAR-1.

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Section: Introductionmentioning

confidence: 99%

Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

Beaulieu

Church

2007

Experimental Cell Research

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“…Na presença do receptor endotelial de proteína C, o zimogênio é convertido em sua forma ativa (PCA) através da interação com o complexo trombina-trombomodulina 19,20 . Uma vez que a fisiopatologia da sepse consiste em interação complexa entre os sistemas de inflamação e coagulação, a eficácia da PCA na sepse grave resulta da combinação de suas propriedades antiinflamatória, antitrombótica e pró-fibrinolítica 19,[21][22][23][24][25] . Na década de 1980, Taylor e col. obtiveram informações preliminares para a compreensão do papel da PCA na sepse.…”

Section: Discussionunclassified

Proteína C ativada no tratamento de recém-nascido com sepse, choque e disfunção de múltiplos órgãos e sistemas: relato de caso e revisão de literatura

Georgetti¹,

Eugénio²

2006

Rev. bras. ter. intensiva

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“…APC has been shown to inhibit the generation of inflammatory cytokines such as TNF-a and to have a selective inhibitory activity on the response of human mononuclear phagocytes to liposaccharide, interferon-y or phorbol ester [6]. By using gene expression profiling, Joyce et al examined the direct effects of APC on endothelial cell function and showed that APC suppressed pro-inflammatory pathways and NF-KB-modulated gene expression [8]. Furthermore, APC promoted anti-apoptotic and cell survival pathways in TNF-a stimulated endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Activated protein C attenuates acute ischaemia reperfusion injury in skeletal muscle

Dillon¹,

Laing²,

Cahill³

et al. 2005

J. Orthop. Res.

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Activated protein C (APC) is an endogenous anti-coagulant with anti-inflammatory properties. The purpose of the present study was to evaluate the effects of activated protein C in the setting of skeletal muscle ischaemia reperfusion injury (IRI). IRI was induced in rats by applying rubber bands above the levels of the greater trochanters bilaterally for a period of 2 h followed by 12 h reperfusion. Treatment groups received either equal volumes of normal saline or activated protein C prior to tourniquet release. Following 12 h reperfusion, muscle function was assessed electrophysiologically by electrical field stimulation. The animals were then sacrificed and skeletal muscle harvested for evaluation.Activated protein C significantly attenuated skeletal muscle reperfusion injury as shown by reduced myeloperoxidase content, wet to dry ratio and electrical properties of skeletal muscle. Further in vitro work was carried out on neutrophils isolated from healthy volunteers to determine the direct effect of APC on neutrophil function. The effects of APC on TNF-u stimulated neutrophils were examined by measuring CD18 expression as well as reactive oxygen species generation. The in vitro work demonstrated a reduction in CD 18 expression and reactive oxygen species generation.We conclude that activated protein C may have a protective role in the setting of skeletal muscle ischaemia reperfusion injury and that this is in part mediated by a direct inhibitory effect on neutrophil activation.

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Gene Expression Profile of Antithrombotic Protein C Defines New Mechanisms Modulating Inflammation and Apoptosis

Cited by 609 publications

References 41 publications

Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

Proteína C ativada no tratamento de recém-nascido com sepse, choque e disfunção de múltiplos órgãos e sistemas: relato de caso e revisão de literatura

Activated protein C attenuates acute ischaemia reperfusion injury in skeletal muscle

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