degradation of blood coagulation factors Va and VIIIa
Synonyms
activated protein c, rhapc, protein ca, anticoagulant activated protein c, autoprothrombin ii-a, anticoagulant-activated protein c, anticoagulant serine protease-activated protein c, ghrelin endopeptidase, protein c (activated), more
both acyl and desacyl ghrelin are hydrolyzed at the peptide bond between Arg15 and Lys16, generating an N-terminal peptide consisting of the first 15 residues
APC anti-coagulant activity is eventually inhibited by the action of the serpins alpha1-antitrypsin and protein C inhibitor, which irreversibly bind and inactivate APC prior to clearance
APC anti-coagulant activity is eventually inhibited by the action of the serpins alpha1-antitrypsin and protein C inhibitor, which irreversibly bind and inactivate APC prior to clearance
a recombinant APC variant (APCN329Q) mimicking the naturally occurring APC-beta plasma glycoform exhibits superior PAR1 proteolysis at a cleavage site that selectively mediates cytoprotective signaling.Mutant APCN329Q also enhances integrin aMb2-dependent PAR1 proteolysis to exert significantly improved anti-inflammatory activity on macrophages compared with wild-type APC
coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice. aPC resistance of factor (f)V due to the R506Q Leiden mutation protects against detrimental anticoagulant effects of aPC therapy but also abrogates the anti-inflammatory and mortality reducing effects of the signaling-selective 5A-aPC variant that has minimal anticoagulant function. aPC resistance of fV Leiden suppresses in vitro regulation of inflammatory gene expression by aPC, overview
Mac-1 inhibition prevents APC attenuation of pro-inflammatory cytokine release from lipopolysaccharide (LPS)-stimulated murine macrophages. Furthermore, APC administration does not significantly reduce mortality in Mac-1 deficient endotoxemic mice, suggestive of an important role for Mac-1-dependent PAR1 activation on myeloid cells for the ability of APC to limit mortality in murine endotoxemia
potent neuroprotection in murine ischemic stroke models is linked to enzyme mutant 3K3A-APC-induced signaling that arises due to APC's cleavage in protease activated receptor 1 at a noncanonical Arg46 site. This cleavage causes biased signaling that provides a major explanation for APC's in vivo mechanism of action for neuroprotective activities. Mice carrying the 46QQ-PAR1 point mutation strongly support the concept that APC-induced, PAR1-dependent biased signaling following Arg46 cleavage is central to APC's in vivo neuroprotective benefits in this model of ischemic stroke
activated protein C is the key effector molecule of the natural protein C pathway. Biological function and mechanism of the protein C pathway in which protein S and the aPC-cleaved form of factor V are cofactors for anti-inflammatory cell signaling by aPC in the context of endotoxemia and infection, overview
other cell receptors, especially endothelial cell protein C (EPCR) and PAR3 inter alia, may also significantly contribute to APC-initiated cell signaling. APC anticoagulant and cell signaling pathways and the structure of signaling-selective 3K3A-APC, overview
activated protein C (APC) is an anticoagulant protease that initiates cell signaling via protease-activated receptor 1 (PAR1) to regulate vascular integrity and inflammatory response. Importance of APC glycosylation in controlling the efficacy of PAR1 proteolysis by APC. Analysis of APC inhibition of cytokine secretion from RAW-264.7 cells. APC-beta exhibits superior inhibition of cerebral injury in murine ischemic stroke
coagulation-independent cell signaling by aPC appears to be the predominant mechanism underlying its highly reproducible therapeutic efficacy in most animal models of injury and infection. Using a mouse model of Staphylococcus aureus sepsis,marked disease stage-specific effects of the anticoagulant and cell signaling functions of aPC are demonstrated. Factor V and protein S are required for sepsis mortality reduction and suppression of inflammatory gene expression by activated protein C. Procofactor V (cleaved by aPC at R506) and protein S are necessary cofactors for the aPC-mediated inhibition of inflammatory tissue-factor signaling. The antiinflammatory cofactor function of fV involves the same structural features that govern its cofactor function for the anticoagulant effects of aPC, yet its anti-inflammatory activities do not involve proteolysis of activated coagulation factors Va and VIIIa. Sepsis stage-related response to infusion of aPC variants, overview. Inhibition of tissue factor-EPCR-PAR2 signaling by enzyme aPC requires protein S and the factor V B domain. aPC inhibits PAR2 activation by the ternary tissue factor-factor VIIa-factor Xa complex
protein C is a plasma serine protease zymogen whose active form, activated protein C (APC), exerts potent anticoagulant activity. In addition to its antithrombotic role as a plasma protease, pharmacologic APC is a pleiotropic protease that activates diverse homeostatic cell signaling pathways via multiple receptors on many cells. Enzyme APC shows cytoprotective and neurogenerative activities which most often, but not always, involve PAR1 and EPCR, often other receptors are required, such as PAR3, sphingosine phosphate 1 receptor 1 (S1P1), the integrin Mac-1 or other beta1 and beta3 integrins, apolipoprotein E receptor 2, epidermal growth factor receptor, and Tie-2 (tunica intima endothelial receptor tyrosine kinase 2). Neuroprotective effects of APC in the neurovascular space and in neurons, overview. APC's neuronal protective actions require PAR1 and PAR3. Enzyme mutant 3K3A-APC promotes neurogenesis in vitro as well as in vivo in the murine middle cerebral artery occlusion stroke model, using human fetal neural stem and progenitor cells
the anticoagulant-activated protein C (APC) acts not solely as a crucial regulator of thrombus formation following vascular injury, but also as a potent signalling enzyme with important functions in the control of both acute and chronic inflammatory disease. Distinct from its crucial role in regulating blood coagulation, APC initiates cell signalling via engagement with multiple cell surface receptors. Although APC triggers an array of signalling pathways via distinct receptor interactions on different cell types, APC signalling is invariably cytoprotective, conferring protection against exposure to pro-inflammatory and/or pro-apoptotic agents. Prototypical APC signalling on endothelial cells involves initial binding to EPCR that in turn facilitates proteolysis and activation of protease-activated receptor 1 (PAR1). APC binding to EPCR is a pre-requisite for PAR3 activation by APC, which mediates similar protective signalling outputs as PAR1 activation. The role of EPCR as an APC co-receptor for PAR1 signalling can also be assumed by the integrin alphaMbeta2 (macrophage-1 antigen, Mac-1)
proteolytic cleavage and activation by thrombin removing the activation peptide, thrombomodulin and endothelial cell protein C receptor PAR-1 are required for efficient enzyme activation
engineering of APC by site-directed mutagenesis provided a signaling selective APC mutant with 3 Lys residues replaced by 3 Ala residues, 3K3A-APC, that lacks over 90% anticoagulant activity but retains normal cell signaling activities. The 3K3A-APC mutant exerts multiple potent neuroprotective activities, which require the G-protein-coupled receptor, protease activated receptor 1 (PAR1). Potent neuroprotection in murine ischemic stroke models is linked to 3K3A-APC-induced signaling that arises due to APC's cleavage in protease activated receptor 1 at a noncanonical Arg46 site
the recombinant APC variant APCN329Q mimics the glycosylation pattern of the endogenous plasma APC-beta glycoform and exhibits significantly enhances PAR1-dependent cytoprotective activity on endothelial cells compared with wild-type APC, determination of the molecular basis for superior APC-beta cytoprotective signaling
human APC variants specifically designed to possess divergent anti-coagulant and signalling properties are created by ablation of a substrate-binding exosite for FVa on the surface of the APC serine protease domain (APC-R229A/R230A, APC-K191A/K192A/K193A and a combination of these mutations, termed 5A-APC). These variants signal normally via EPCR-PAR1 on endothelial cells, but possess severely attenuated ability to degrade FVa and thus inhibit coagulation. In animal models of endotoxemia, APC-5A exhibits comparable ability to protect mice from LPS-induced lethality as wild-type APC, illustrating the limited requirement for APC anti-coagulant function to reduce LPS-mediated mortality, at least in mice. These mutant variants are also shown to be equally protective in rodent models of ischaemic stroke and APC-K191A/K192A/K193A (APC-3K3A) is assessed in a phase II clinical trial as an adjunctive neuroprotective therapy in combination with t-PA (EC 3.4.21.68) postischaemic stroke
neuroprotective activity of a murine APC variant with limited anticoagulant activity (mAPCPS) is compared with an identical APC variant except for the absence of glycosylation at the APC-beta sequon (mAPCPS/N329Q). mAPCPS/N329Q limits cerebral ischemic injury and reduces brain lesion volume significantly more effectively than mAPCPS
neuroprotective activity of a murine APC variant with limited anticoagulant activity (mAPCPS) is compared with an identical APC variant except for the absence of glycosylation at the APC-beta sequon (mAPCPS/N329Q). mAPCPS/N329Q limits cerebral ischemic injury and reduces brain lesion volume significantly more effectively than mAPCPS
protective effect of recombinant APC administration in animals subject to Escherichia coli-induced sepsis. Possible effects of APC administration may include attenuation of the proinflammatory cytokine storm, re-balancing dysregulated haemostasis or degradation of cytotoxic extracellular histones that circulate during sepsis. Successful pre-clinical animal studies indicate that the neuroprotective effects of recombinant APC do not require anti-coagulant activity for therapeutic benefit to be achieved. The bleeding risk associated with the use of recombinant APC in the treatment of severe sepsis and apparent lack of requirement for APC anti-coagulant function for protective activity in murine endotoxemia and stroke models prompted the development of APC variants with selectively diminished anti-coagulant activity. APC variants that possess limited anti-coagulant function but normal cytoprotective signalling activity represent a potentially safer alternative to recombinant wild-type APC in disease settings in which APC has been shown to be protective