Brain-Specific Protein C Activation During Carotid Artery Occlusion in Humans

Macko, Richard F.; Killewich, Lois A.; Fernández, José A.; Cox, D. Kim; Gruber, András; Griffin, John H.

doi:10.1161/01.str.30.3.542

Cited by 31 publications

(22 citation statements)

References 43 publications

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“…This finding is unique, because such potential consumption of APC has not been previously reported in a clinical situation. This potential 280-fold increase in protein C activation in the liver graft would be the most localized and pronounced enhancement of protein C pathway thus far implicated in human beings, differing from respective activation in brain (20,23) and myocardial (12) reperfusion. In both the latter cases, moderate formation of APC was observed in the reperfused vascular bed without concomitant measurable decrease in protein C level.…”

Section: Discussionmentioning

confidence: 92%

Activation of protein C during reperfusion in clinical liver transplantation

Ilmakunnas

Petäjä²,

Höckerstedt³

et al. 2003

Transplantation

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Despite protein C deficiency, patients with liver insufficiency are able to maintain normal APC levels. During reperfusion, protein C consumption occurs in the liver without concomitant hepatic release of APC, indicating a shortage of APC in the reperfused liver. The process consuming protein C and APC may be related to the simultaneous ongoing neutrophil and monocyte activation within the liver graft, indicating a regulatory role for APC in inflammation.

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Section: Discussionmentioning

confidence: 92%

Activation of protein C during reperfusion in clinical liver transplantation

Ilmakunnas

Petäjä²,

Höckerstedt³

et al. 2003

Transplantation

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“…These observations are consistent with the hypothesis that the protein C pathway plays a protective role against ischemic stroke. To test the hypothesis that brain ischemia induces generation of APC as a protective response, we determined levels of protein C zymogen and circulating APC in patients undergoing routine carotid endarterectomy (36). When levels of these plasma analytes were determined in radial arterial and internal jugular blood samples before, during, and after the carotid endarterectomy, we observed that brain ischemia during the occlusion resulted in augmentation of circulating APC in the jugular venous blood, whereas there were no changes in radial arterial blood ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Activated protein C and ischemic stroke

Griffin

Fernández

Liu

et al. 2004

Critical Care Medicine

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“…34 TM expression has been demonstrated in brain vessels, because TM mRNA expression is present in the blood-brain barrier 35 and protein C is activated in jugular vein blood during carotid artery occlusion in humans. 36 The endothelial TM expression in brain is constitutively downregulated by astrocytes and acutely downregulated by pathogenic mediators of ischemic stroke, such as interleukin-1␤ and tumor necrosis factor-␣. 35 Interestingly, astrocyteinduced downregulation of TM endothelial expression occurs through transforming growth factor-␤ secretion, 37 known to enhance endothelial cell proliferation.…”

Section: Erk2mentioning

confidence: 99%

Thrombomodulin Prolongs Thrombin-Induced Extracellular Signal–Regulated Kinase Phosphorylation and Nuclear Retention in Endothelial Cells

Olivot

Estebanell

Lafay

et al. 2001

Circulation Research

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Abstract-On endothelial cells, thrombin binds to thrombomodulin (TM), an integral membrane-bound glycoprotein, and to protease-activated receptors (PARs). Thrombin binding to TM modulates endothelial cell and smooth muscle cell proliferation mediated through PAR1. We studied the phosphorylation and nuclear translocation of extracellular signal-regulated kinases (ERKs) 1 and 2 in human umbilical vein endothelial cells activated by thrombin. Thrombin and thrombin receptor-activating peptide (TRAP)-induced DNA synthesis were significantly inhibited by PD98059, an inhibitor of ERK phosphorylation. Immunoblots of phosphorylated ERKs (pERKs) and immunocytochemical studies of pERK localization revealed differences in the signal generated by thrombin and TRAP. After a short activation (15 minutes), the phosphorylation and the intracellular localization of pERKs were the same with the 2 agonists. After 4 hours, however, pERKs were visualized in the nuclei of thrombin-activated cells but barely detectable in TRAP-activated cells. Moreover, after 4 hours, the pERKs were visualized in the nuclei of cells stimulated by TRAP in the presence of a thrombin mutant that bound to TM, whereas they were around the nuclei in cells stimulated by thrombin in the presence of a monoclonal antibody preventing thrombin binding to TM. The results demonstrate that ERKs are involved in human umbilical vein endothelial cell DNA synthesis mediated by PAR agonists, that the duration of pERK nuclear retention is in inverse ratio to the mitogenic response, and that in addition to its role in the regulation of blood coagulation, TM acts as a thrombin receptor that modulates the duration of pERK nuclear retention and cell proliferation in response to thrombin. T hrombin is a multifunctional serine protease generated at sites of vascular injury. Thrombin plays a key role in blood coagulation and thrombotic disorders. It acts as the central enzyme of the coagulation cascade by cleaving fibrinogen into fibrin and favoring its own production by activating several coagulation factors by limited proteolysis. Thrombin also regulates its own formation after binding to thrombomodulin (TM), an integral membrane-bound glycoprotein expressed on endothelial cells. TM acts as a cofactor of thrombin to activate protein C, a serine protease ensuring proteolytic inactivation of 2 coagulation factors, factor Va and factor VIIIa. Thrombin also interacts with a variety of cells mediating inflammatory and proliferative responses to vascular injury. 1 For all protein and cellular interactions, thrombin has a recognition site and a catalytic active site. By the former, called the anion-binding exosite (ABE1), thrombin binds to specific negatively charged sequences. By the catalytic site, thrombin exerts its proteolytic activity. 2 On vascular endothelial cells, thrombin ABE1 binds to TM. This binding occurs through the epithelial growth factor (EGF)-like domains 4 and 5 of TM. 3 Thrombin ABE1 also binds to the typical heptahelical thrombin receptor, the first member of pr...

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Brain-Specific Protein C Activation During Carotid Artery Occlusion in Humans

Cited by 31 publications

References 43 publications

Activation of protein C during reperfusion in clinical liver transplantation

Activation of protein C during reperfusion in clinical liver transplantation

Activated protein C and ischemic stroke

Thrombomodulin Prolongs Thrombin-Induced Extracellular Signal–Regulated Kinase Phosphorylation and Nuclear Retention in Endothelial Cells

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